2024-03-28T17:32:38Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/86862019-08-30T11:25:06Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Bode, Helge Björn
author
Müller, Rolf
2007-02-21T08:24:41Z
2003-07
Plant Physiology 2003 132(3):1153-1161
0032-0889
12857798
10.1104/pp.102.019760
http://hdl.handle.net/10033/8686
526270
en_US
Copyright © 2003, The American Society for Plant
Biologists
Possibility of Bacterial Recruitment of Plant Genes Associated with the Biosynthesis of Secondary Metabolites1
URL
https://hzi.openrepository.com/bitstream/10033/8686/1/Bode%20and%20M%c3%bcller_final.pdf
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Bode and Müller_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/8686/7/Bode%20and%20M%c3%bcller_final.pdf.txt
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Bode and Müller_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/146282019-08-30T11:27:16Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Siegert, Jeannette
author
Sastalla, Inka
author
Chhatwal, Gursharan Singh
author
Medina, Eva
2007-11-19T13:54:12Z
2006-02-01
Microbes Infect. 2006, 8(2):347-53
1286-4579
16213175
10.1016/j.micinf.2005.06.024
http://hdl.handle.net/10033/14628
There is substantial evidence that host genetic factors are important in determining susceptibility to infection with group A streptococci (GAS). Several studies have revealed that, similarly to humans, a genetic component may be important in determining susceptibility to GAS infection in mice. Thus, C3H/HeN mice are much more susceptible to streptococcal infection than BALB/c mice. We have determined here whether vaccination makes genetically susceptible mice as capable as genetically resistant mice to control GAS infection. Resistant BALB/c and susceptible C3H/HeN mice were immunized either systemically with heat-killed GAS or through the mucosal route with an M protein-based subunit vaccine, and challenged with live bacteria. Vaccination elicited in both mouse strains similar levels of bactericidal anti-GAS IgG antibodies and also antigen-specific mucosal IgA. Vaccination provided mice of both strains with an increased and equal capacity to express immunity against GAS as indicated by the reduced level of bacteria in the organs and the ability of vaccinated mice to survive infection. Protection in vaccinated mice was dependent on the presence of T cell-dependent bactericidal antibodies as shown by the ability of serum elicited in immunocompetent mice but not of serum elicited in T cell-deficient nu/nu mice to passively transfer anti-GAS immunity. In conclusion, the results presented here demonstrated that the presence of anti-GAS specific, T cell-dependent bactericidal antibodies elicited after vaccination overcomes the innate genetic susceptibility of C3H/HeN mice and makes both resistant and susceptible mice equally capable of controlling GAS infection.
en
Vaccination equally enables both genetically susceptible and resistant mice to control infection with group A streptococci.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/14628/1/Siegert%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/14628/5/Siegert%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/195322019-08-30T11:25:43Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Goldmann, Oliver
author
von Köckritz-Blickwede, Maren
author
Höltje, Claudia
author
Chhatwal, Gursharan S
author
Geffers, Robert
author
Medina, Eva
department
Infection Immunology Research Group, Helmholtz Center for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
2008-03-03T13:32:53Z
2007-08
Transcriptome analysis of murine macrophages in response to infection with Streptococcus pyogenes reveals an unusual activation program. 2007, 75 (8):4148-57 Infect. Immun.
0019-9567
17526748
10.1128/IAI.00181-07
http://hdl.handle.net/10033/19532
Infection and immunity
The complex response of murine macrophages to infection with Streptococcus pyogenes was investigated at the level of gene expression with a high-density oligomer microarray. More than 400 genes were identified as being differentially regulated. Many of the up-regulated genes encode molecules involved in the immune response and in inflammation, transcription, signaling, apoptosis, the cell cycle, electron transport, and cell adhesion. Of particular interest was the up-regulation of proinflammatory cytokines, typical of the classically activated macrophages (M1 phenotype), such as tumor necrosis factor alpha, interleukin 1 (IL-1), and IL-6, and as well as the up-regulation of anti-inflammatory mediators, such as IL-1 decoy receptor and IL-10, associated with alternative macrophage activation (M2 phenotype). Furthermore, the gene encoding inducible nitric oxide synthase (iNOS), an enzyme typically implicated in classical activation, was not induced in infected macrophages. Instead, the gene encoding arginase, a competitor for the iNOS substrate arginine involved in the alternative activation pathway, was up-regulated in S. pyogenes-infected cells. Thus, the microarray-based gene expression analysis demonstrated that S. pyogenes induces an atypical activation program in macrophages, with some but not all features of the classical or alternative activation phenotypes. The microarray data also suggested that the bactericidal activity of macrophages against S. pyogenes is mediated by phagocyte oxidase, as p47phox was up-regulated in infected cells. Indeed, the in vivo and in vitro killing of S. pyogenes was markedly diminished in the absence of functional phagocyte (p47(phox-/-)) but not in the absence of iNOS (iNOS(-/-)). An understanding of how macrophages respond to S. pyogenes at the molecular level may facilitate the development of new therapeutic paradigms.
en
Transcriptome analysis of murine macrophages in response to infection with Streptococcus pyogenes reveals an unusual activation program.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/19532/1/Goldmann%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/234722019-08-30T11:37:23Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
von Köckritz-Blickwede, Maren
author
Goldmann, Oliver
author
Thulin, Pontus
author
Heinemann, Katja
author
Norrby-Teglund, Anna
author
Rohde, Manfred
author
Medina, Eva
department
Infection Immunology Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany.
2008-04-15T13:36:28Z
2008-03-15
Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. 2008, 111 (6):3070-80 Blood
0006-4971
18182576
10.1182/blood-2007-07-104018
http://hdl.handle.net/10033/23472
Blood
These days it has been increasingly recognized that mast cells (MCs) are critical components of host defense against pathogens. In this study, we have provided the first evidence that MCs can kill bacteria by entrapping them in extracellular structures similar to the extracellular traps described for neutrophils (NETs). We took advantage of the ability of MCs to kill the human pathogen Streptococcus pyogenes by a phagocytosis-independent mechanism in order to characterize the extracellular antimicrobial activity of MCs. Close contact of bacteria and MCs was required for full antimicrobial activity. Immunofluorescence and electron microscopy revealed that S pyogenes was entrapped by extracellular structures produced by MCs (MCETs), which are composed of DNA, histones, tryptase, and the antimicrobial peptide LL-37. Disruption of MCETs significantly reduced the antimicrobial effect of MCs, suggesting that intact extracellular webs are critical for effective inhibition of bacterial growth. Similar to NETs, production of MCETs was mediated by a reactive oxygen species (ROS)-dependent cell death mechanism accompanied by disruption of the nuclear envelope, which can be induced after stimulation of MCs with phorbol-12-myristate-13-acetate (PMA), H(2)O(2), or bacterial pathogens. Our study provides the first experimental evidence of antimicrobial extracellular traps formation by an immune cell population other than neutrophils.
en
Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/23472/1/von%20Kockritz-Blickwede_final.pdf
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https://hzi.openrepository.com/bitstream/10033/23472/8/von%20Kockritz-Blickwede_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/243722019-08-30T11:33:57Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Klein, Christian
author
Medina, Eva
author
Sander, Leif
author
Dierssen, Uta
author
Roskams, Tania
author
Mueller, Werner
author
Trautwein, Christian
author
Goldmann, Oliver
department
Medizinische Klinik III, University Hospital Aachen, Rheinisch-Westfalisch Techniche Hochschule Aachen, Aachen, Germany. christian.klein@dife.de
2008-04-29T09:14:07Z
2007-09-01
Contribution of interleukin-6/gp 130 signaling in hepatocytes to the inflammatory response in mice infected with Streptococcus pyogenes. 2007, 196 (5):755-62 J. Infect. Dis.
0022-1899
17674319
10.1086/520090
http://hdl.handle.net/10033/24372
The Journal of infectious diseases
BACKGROUND: Sepsis and septic shock caused by gram-positive bacteria have become increasingly frequent clinical problems. These conditions are accompanied by an overwhelming inflammation in which the liver plays a central role as a source and target of inflammatory mediators. Sepsis is still associated with high mortality rates, and new intervention strategies directed at ameliorating the extent of the inflammatory reaction are strongly needed. Here, we investigated whether blockage of the transducer gp130, a receptor involved in the regulation of the inflammatory response, might be useful in the treatment of experimental gram-positive sepsis. METHODS: An experimental model of gram-positive sepsis was used in which liver-specific gp130-deficient mice (FVB/n alfpCre+ gp130(LoxP/LoxP)) and wild-type mice (FVB/n gp130(LoxP/LoxP)) were intravenously infected with Streptococcus pyogenes. The following parameters were monitored: mortality, bacterial loads in systemic organs, serum inflammatory cytokine levels, and organ damage. RESULTS: We show that infected gp130-deficient mice survived significantly longer, had lower bacterial loads, and developed organ damage more slowly than infected wild-type mice. Furthermore, levels of interferon- gamma , interleukin-6, and the chemokine cytokine-induced neutrophil chemoattractant were significantly lower in gp130-deficient mice than in wild-type mice. Histopathological examination of livers showed lower amounts of neutrophil infiltration, apoptosis, and tissue damage in infected gp130-deficient mice than in wild-type mice. CONCLUSION: Our results demonstrate that the gp130 receptor is involved in the regulation of inflammation during gram-positive sepsis and that blockage of gp130 signaling in hepatocytes could constitute a novel target for adjunctive therapy in patients with sepsis.
en
Contribution of interleukin-6/gp 130 signaling in hepatocytes to the inflammatory response in mice infected with Streptococcus pyogenes.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/24372/1/Klein%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/483142019-08-30T11:30:58Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Loof, Torsten G
author
Goldmann, Oliver
author
Medina, Eva
department
Infection Immunology Research Group, Department of Microbial Pathogenesis, Helmholtz Center for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
2009-02-02T08:57:16Z
2008-06
Immune recognition of Streptococcus pyogenes by dendritic cells. 2008, 76 (6):2785-92 Infect. Immun.
1098-5522
18391010
10.1128/IAI.01680-07
http://hdl.handle.net/10033/48314
Infection and immunity
Streptococcus pyogenes is one of the most frequent human pathogens. Recent studies have identified dendritic cells (DCs) as important contributors to host defense against S. pyogenes. The objective of this study was to identify the receptors involved in immune recognition of S. pyogenes by DCs. To determine whether Toll-like receptors (TLRs) were involved in DC sensing of S. pyogenes, we evaluated the response of bone marrow-derived DCs obtained from mice deficient in MyD88, an adapter molecule used by almost all TLRs, following S. pyogenes stimulation. Despite the fact that MyD88(-/-) DCs did not differ from wild-type DCs in the ability to internalize and kill S. pyogenes, the up-regulation of maturation markers, such as CD40, CD80, and CD86, and the production of inflammatory cytokines, such as interleukin-12 (IL-12), IL-6, and tumor necrosis factor alpha, were dramatically impaired in S. pyogenes-stimulated MyD88(-/-) DCs. These results suggest that signaling through TLRs is the principal pathway by which DCs sense S. pyogenes and become activated. Surprisingly, DCs deficient in signaling through each of the TLRs reported as potential receptors for gram-positive cell components, such as TLR1, TLR2, TLR4, TLR9, and TLR2/6, were not impaired in the secretion of proinflammatory cytokines and the up-regulation of costimulatory molecules after S. pyogenes stimulation. In conclusion, our results exclude a major involvement of a single TLR or the heterodimer TLR2/6 in S. pyogenes sensing by DCs and argue for a multimodal recognition in which a combination of several different TLR-mediated signals is essential for a rapid and effective response to the pathogen.
en
Immune recognition of Streptococcus pyogenes by dendritic cells.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/48314/1/Loof%20et%20al_final.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/48314/7/Loof%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/980202019-08-30T11:25:11Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Goldmann, Oliver
author
Lehne, Sabine
author
Medina, Eva
department
Infection Immunology Research Group, Department of Microbial Pathogenesis, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany.
2010-05-06T09:45:30Z
2010-04
Age-related susceptibility to Streptococcus pyogenes infection in mice: underlying immune dysfunction and strategy to enhance immunity. 2010, 220 (5):521-9 J. Pathol.
1096-9896
20020512
10.1002/path.2664
http://hdl.handle.net/10033/98020
The Journal of pathology
Epidemiological studies have shown that the elderly are at higher risk of severe Streptococcus pyogenes infections. In this study, we used a mouse model that displays the age-related loss of resistance to S. pyogenes infection seen in humans to investigate the impaired immune mechanism underlying the age-associated susceptibility to this pathogen. Young (2-3 months old) and aged (>20 months old) BALB/c mice were subcutaneously or intravenously inoculated with S. pyogenes and their capacity to control infection was compared. Aged mice showed faster progression of disease, earlier morbidity, and increased mortality when compared with young animals. Since macrophages are critical for host defence against S. pyogenes, we investigated whether susceptibility of aged mice may be due to an age-associated decline in the functionality of these cells. Our results showed that macrophages from aged mice were as capable as those from young animals to uptake and kill S. pyogenes, but the number of resident tissue macrophages was significantly reduced in the aged host. Treatment of aged mice with macrophage colony-stimulating factor (M-CSF) significantly increased the number of resident macrophages and improved their response to infection. Our results indicate that treatment with M-CSF can restore, at least in part, the mechanisms affected by immunosenescence and enhance the natural resistance of aged mice to infection with S. pyogenes.
en
Age-related susceptibility to Streptococcus pyogenes infection in mice: underlying immune dysfunction and strategy to enhance immunity.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/98020/1/Goldmann%20et%20al_final.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/98020/7/Goldmann%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/1220862019-08-30T11:27:09Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Weissman, Kira J
author
Müller, Rolf
department
Helmholtz Institute for Pharmaceutical Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
2011-02-16T13:15:41Z
2010-09-18
Myxobacterial secondary metabolites: bioactivities and modes-of-action. 2010, 27 (9):1276-95 Nat Prod Rep
1460-4752
20520915
10.1039/c001260m
http://hdl.handle.net/10033/122086
Natural product reports
en
Myxobacterial secondary metabolites: bioactivities and modes-of-action.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/122086/1/Weissmann_M%c3%bcller_final.pdf
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oai:repository.helmholtz-hzi.de:10033/2039692019-08-30T11:36:32Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Nippe, Nadine
author
Varga, Georg
author
Holzinger, Dirk
author
Löffler, Bettina
author
Medina, Eva
author
Becker, Karsten
author
Roth, Johannes
author
Ehrchen, Jan M
author
Sunderkötter, Cord
department
Institute of Immunology, University of Muenster, Muenster, Germany.
2012-01-20T14:48:05Z
2011-01
Subcutaneous infection with S. aureus in mice reveals association of resistance with influx of neutrophils and Th2 response. 2011, 131 (1):125-32 J. Invest. Dermatol.
1523-1747
20882039
10.1038/jid.2010.282
http://hdl.handle.net/10033/203969
The Journal of investigative dermatology
Staphylococcus aureus is the leading cause of bacterial skin infection. Once it overcomes the epithelial barrier, it either remains locally controlled or spreads in the dermis causing soft tissue infection. These different courses depend not only on its virulence factors, but also on the immune response of the infected individual. The goal of this study was to identify host factors that influence different outcomes. We, therefore, established comparative analysis of subcutaneous footpad infection with S. aureus (SH1000) in different inbred mouse strains. We found that C57BL/6 mice are more susceptible than BALB/c and DBA/2 mice, reflected by significantly higher footpad swelling and bacterial load, as well as increased dissemination of bacteria into inguinal lymph nodes and kidneys. This susceptibility was associated with lower influx of polymorphonuclear leukocytes (PMNs), but higher secretion of CXCL-2. Remarkably, resistance correlated with S. aureus-specific Th2-cell response in BALB/c and DBA/2 mice, whereas susceptible C57BL/6 mice generated a Th1-cell response. As Th1 cells are able to induce release of CXCL-2, and as CXCL-2 is able to increase the survival of S. aureus within PMNs, interactions between PMNs and Th1 or Th2 cells need to be considered as important mechanisms of resistance in murine soft tissue infection with S. aureus.
en
Subcutaneous infection with S. aureus in mice reveals association of resistance with influx of neutrophils and Th2 response.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/203969/1/Nippe%20et%20al_final.pdf
File
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URL
https://hzi.openrepository.com/bitstream/10033/203969/7/Nippe%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/1463762019-08-30T11:37:00Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Kopp, Maren
author
Irschik, Herbert
author
Gemperlein, Katja
author
Buntin, Kathrin
author
Meiser, Peter
author
Weissman, Kira J
author
Bode, Helge B
author
Müller, Rolf
department
Helmholtz Institute for Pharmaceutical Research, Helmholtz Center for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, PO Box 151150, 66041 Saarbrücken, Germany.
2011-10-21T12:35:38Z
2011-05
Insights into the complex biosynthesis of the leupyrrins in Sorangium cellulosum So ce690. 2011, 7 (5):1549-63 Mol Biosyst
1742-2051
21365089
10.1039/c0mb00240b
http://hdl.handle.net/10033/146376
Molecular bioSystems
The anti-fungal leupyrrins are secondary metabolites produced by several strains of the myxobacterium Sorangium cellulosum. These intriguing compounds incorporate an atypically substituted γ-butyrolactone ring, as well as pyrrole and oxazolinone functionalities, which are located within an unusual asymmetrical macrodiolide. Previous feeding studies revealed that this novel structure arises from the homologation of four distinct structural units, nonribosomally-derived peptide, polyketide, isoprenoid and a dicarboxylic acid, coupled with modification of the various building blocks. Here we have attempted to reconcile the biosynthetic pathway proposed on the basis of the feeding studies with the underlying enzymatic machinery in the S. cellulosum strain So ce690. Gene products can be assigned to many of the suggested steps, but inspection of the gene set provokes the reconsideration of several key transformations. We support our analysis by the reconstitution in vitro of the biosynthesis of the pyrrole carboxylic starter unit along with gene inactivation. In addition, this study reveals that a significant proportion of the genes for leupyrrin biosynthesis are located outside the core cluster, a 'split' organization which is increasingly characteristic of the myxobacteria. Finally, we report the generation of four novel deshydroxy leupyrrin analogues by genetic engineering of the pathway.
en
Insights into the complex biosynthesis of the leupyrrins in Sorangium cellulosum So ce690.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/146376/1/Kopp%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/2146692019-08-30T11:31:49Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Abel, Jens
author
Goldmann, Oliver
author
Ziegler, Christina
author
Höltje, Claudia
author
Smeltzer, Mark S
author
Cheung, Ambrose L
author
Bruhn, Daniela
author
Rohde, Manfred
author
Medina, Eva
department
Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
2012-03-07T15:14:34Z
2011
Staphylococcus aureus evades the extracellular antimicrobial activity of mast cells by promoting its own uptake. 2011, 3 (5):495-507 J Innate Immun
1662-8128
21654154
10.1159/000327714
http://hdl.handle.net/10033/214669
Journal of innate immunity
In this study, we investigated the interactions of Staphylococcus aureus with mast cells, which are multifunctional sentinels lining the surfaces of the body. We found that bone marrow-derived murine mast cells (BMMC) exerted a powerful phagocytosis-independent antimicrobial activity against S. aureus. Both the release of extracellular traps as well as discharge of antimicrobial compounds were the mechanisms used by the BMMC to kill extracellular S. aureus. This was accompanied by the secretion of mediators such as TNF-α involved in the recruitment of effector cells. Interestingly, S. aureus subverted the extracellular antimicrobial activity of the BMMC by internalizing within these cells. S. aureus was also capable to internalize within human mast cells (HMC-1) and within murine skin mast cells during in vivo infection. Bacteria internalization was, at least in part, mediated by the α5β1 integrins expressed on the surface of the mast cell. In the intracellular milieu, the bacterium survived and persisted by increasing the cell wall thickness and by gaining access into the mast cell cytosol. The expression of α-hemolysin was essential for staphylococci intracellular persistence. By hiding within the long-life mast cells, staphylococci not only avoid clearance but also establish an infection reservoir that could contribute to chronic carriage.
en
Staphylococcus aureus evades the extracellular antimicrobial activity of mast cells by promoting its own uptake.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/214669/1/Abel%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/2515592019-08-30T11:24:31Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Pommerenke, Claudia
author
Wilk, Esther
author
Srivastava, Barkha
author
Schulze, Annika
author
Novoselova, Natalia
author
Geffers, Robert
author
Schughart, Klaus
department
Department of Infection Genetics, Helmholtz Centre for Infection Research and University of Veterinary Medicine Hannover, Braunschweig, Germany.
2012-11-09T12:36:20Z
2012
Global transcriptome analysis in influenza-infected mouse lungs reveals the kinetics of innate and adaptive host immune responses. 2012, 7 (7):e41169 PLoS ONE
1932-6203
22815957
10.1371/journal.pone.0041169
http://hdl.handle.net/10033/251559
PloS one
An infection represents a highly dynamic process involving complex biological responses of the host at many levels. To describe such processes at a global level, we recorded gene expression changes in mouse lungs after a non-lethal infection with influenza A virus over a period of 60 days. Global analysis of the large data set identified distinct phases of the host response. The increase in interferon genes and up-regulation of a defined NK-specific gene set revealed the initiation of the early innate immune response phase. Subsequently, infiltration and activation of T and B cells could be observed by an augmentation of T and B cell specific signature gene expression. The changes in B cell gene expression and preceding chemokine subsets were associated with the formation of bronchus-associated lymphoid tissue. In addition, we compared the gene expression profiles from wild type mice with Rag2 mutant mice. This analysis readily demonstrated that the deficiency in the T and B cell responses in Rag2 mutants could be detected by changes in the global gene expression patterns of the whole lung. In conclusion, our comprehensive gene expression study describes for the first time the entire host response and its kinetics to an acute influenza A infection at the transcriptome level.
en
Archived with thanks to PloS one
Global transcriptome analysis in influenza-infected mouse lungs reveals the kinetics of innate and adaptive host immune responses.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/251559/1/Pommerenke%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/2669122019-08-30T11:28:24Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Wiedmann, Romina M
author
von Schwarzenberg, Karin
author
Palamidessi, Andrea
author
Schreiner, Laura
author
Kubisch, Rebekka
author
Liebl, Johanna
author
Schempp, Christina
author
Trauner, Dirk
author
Vereb, Gyorgy
author
Zahler, Stefan
author
Wagner, Ernst
author
Müller, Rolf
author
Scita, Giorgio
author
Vollmar, Angelika M
department
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
2013-01-24T15:23:39Z
2012-11-15
The V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1. 2012, 72 (22):5976-87 Cancer Res.
1538-7445
22986742
10.1158/0008-5472.CAN-12-1772
http://hdl.handle.net/10033/266912
Cancer research
The abundance of the multimeric vacuolar ATP-dependent proton pump, V-ATPase, on the plasma membrane of tumor cells correlates with the invasiveness of the tumor cell, suggesting the involvement of V-ATPase in tumor metastasis. V-ATPase is hypothesized to create a proton efflux leading to an acidic pericellular microenvironment that promotes the activity of proinvasive proteases. An alternative, not yet explored possibility is that V-ATPase regulates the signaling machinery responsible for tumor cell migration. Here, we show that pharmacologic or genetic reduction of V-ATPase activity significantly reduces migration of invasive tumor cells in vitro. Importantly, the V-ATPase inhibitor archazolid abrogates tumor dissemination in a syngeneic mouse 4T1 breast tumor metastasis model. Pretreatment of cancer cells with archazolid impairs directional motility by preventing spatially restricted, leading edge localization of epidermal growth factor receptor (EGFR) as well as of phosphorylated Akt. Archazolid treatment or silencing of V-ATPase inhibited Rac1 activation, as well as Rac1-dependent dorsal and peripheral ruffles by inhibiting Rab5-mediated endocytotic/exocytotic trafficking of Rac1. The results indicate that archazolid effectively decreases metastatic dissemination of breast tumors by impairing the trafficking and spatially restricted activation of EGFR and Rho-GTPase Rac1, which are pivotal for directed movement of cells. Thus, our data reveals a novel mechanism underlying the role of V-ATPase in tumor dissemination.
en
Archived with thanks to Cancer research
The V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1.
Article
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oai:repository.helmholtz-hzi.de:10033/2690322019-08-30T11:26:13Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Goldmann, Oliver
author
Medina, Eva
department
Infection Immunology Research Group, Helmholtz Centre for Infection Research Braunschweig, Germany.
2013-02-11T15:37:53Z
2012
The expanding world of extracellular traps: not only neutrophils but much more. 2012, 3:420 Front Immunol
1664-3224
23335924
10.3389/fimmu.2012.00420
http://hdl.handle.net/10033/269032
Frontiers in immunology
The release of extracellular traps (ETs) is a recently described mechanism of innate immune response to infection. Although ETs have been intensely investigated in the context of neutrophil antimicrobial effector mechanisms, other immune cells such as mast cells, eosinophils, and macrophages can also release these structures. The different ETs have several features in common, regardless of the type of cells from which they originated, including a DNA backbone with embedded antimicrobial peptides, proteases, and histones. However, they also exhibit remarkable individual differences such as the type of sub-cellular compartments from where the DNA backbone originates (e.g., nucleus or mitochondria), the proportion of responding cells within the pool, and/or the molecular mechanism/s underlying the ETs formation. This review summarizes the knowledge accumulated in recent years regarding the complex and expanding world of ETs and their role in immune function with particular emphasis on the role of other immune cells rather than on neutrophils exclusively.
en
Archived with thanks to Frontiers in immunology
The expanding world of extracellular traps: not only neutrophils but much more.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/269032/1/Goldmann%20and%20Medina_final.pdf
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oai:repository.helmholtz-hzi.de:10033/2709212019-08-30T11:30:58Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Kaufmann, Katrin
author
Simmons, Luke
author
Herrmann, Jennifer
author
Schwär, Gertrud
author
Luniak, Nora
author
Müller, Rolf
department
Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany. kaufm@uni-trier.de
2013-03-04T13:38:31Z
2013-01
Activity-guided screening of bioactive natural compounds implementing a new glucocorticoid-receptor-translocation assay and detection of new anti-inflammatory steroids from bacteria. 2013, 35 (1):11-20 Biotechnol. Lett.
1573-6776
22983717
10.1007/s10529-012-1042-0
http://hdl.handle.net/10033/270921
Biotechnology letters
Using an in vitro cell-based assay in a flow-design, we have applied activity-guided screening to search for new bioactive compounds isolated from microorganisms. A first assay employs the stable expression of nuclear factor kappa B (NF-κB) while a second assay utilizes the glucocorticoid receptor (GR) coupled to green fluorescent protein. A specialized assay was implemented for both the translocation of NF-κB and to inhibit the translocation of cytokine-mediated NF-κB. In addition, we developed in a wide palette of cell lines used for a highly specialized GR-translocation assay to detect anti-inflammatory effects. This approach demonstrates the straight-forward combination of cell-based assays arranged with an automated fluorescence microscope. This allows for the direct sorting of extracts which are acting in a pharmaceutically interesting way. Initial results using this technique have led to the detection of new anti-inflammatory steroids from bacterial crude extracts.
en
Archived with thanks to Biotechnology letters
Activity-guided screening of bioactive natural compounds implementing a new glucocorticoid-receptor-translocation assay and detection of new anti-inflammatory steroids from bacteria.
Article
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https://hzi.openrepository.com/bitstream/10033/270921/1/Kaufmann%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/2761642019-08-30T11:33:57Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Takacs, Constantin N
author
Hocking, Jason
author
Cabeen, Matthew T
author
Bui, Nhat Khai
author
Poggio, Sebastian
author
Vollmer, Waldemar
author
Jacobs-Wagner, Christine
department
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America.
2013-03-27T13:53:38Z
2013
Growth Medium-Dependent Glycine Incorporation into the Peptidoglycan of Caulobacter crescentus. 2013, 8 (2):e57579 PLoS ONE
1932-6203
23469030
10.1371/journal.pone.0057579
http://hdl.handle.net/10033/276164
PloS one
The peptidoglycan (PG) is a macromolecular component of the bacterial cell wall that maintains the shape and integrity of the cell. The PG of , unlike that of many other Gram-negative bacteria, has repeatedly been shown to contain significant amounts of glycine. This compositional peculiarity has been deemed an intrinsic characteristic of this species. By performing a comprehensive qualitative and quantitative analysis of the PG by high-performance liquid chromatography (HPLC) and mass spectrometry (MS), we show here that glycine incorporation into the PG depends on the presence of exogenous glycine in the growth medium. High levels of glycine were detected at the fifth position of the peptide side chains of PG isolated from cells grown in the complex laboratory medium PYE or in defined medium (M2G) supplemented with casamino acids or glycine alone. In contrast, glycine incorporation was undetectable when cells were grown in M2G medium lacking glycine. Remarkably, glycine incorporation into peptidoglycan occurred even in the presence of low millimolar to sub-millimolar concentrations of free glycine. High glycine content in the PG had no obvious effects on growth rates, mode of PG incorporation or cell morphology. Hence, the PG is able to retain its physiological functions in cell growth and morphogenesis despite significant alterations in its composition, in what we deem to be unprecedented plasticity.
en
Archived with thanks to PloS one
Growth Medium-Dependent Glycine Incorporation into the Peptidoglycan of Caulobacter crescentus.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/276164/1/Takacs_et%20al_final.pdf
File
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URL
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oai:repository.helmholtz-hzi.de:10033/2950522019-08-30T11:26:42Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Rosendahl, Alva
author
Bergmann, Simone
author
Hammerschmidt, Sven
author
Goldmann, Oliver
author
Medina, Eva
department
Infection Immunology Research Group, Department of Medical Microbiology, Helmholtz Centre for Infection Research Braunschweig, Germany.
2013-07-02T14:25:10Z
2013
Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia. 2013, 3:21 Front Cell Infect Microbiol
2235-2988
23802100
10.3389/fcimb.2013.00021
http://hdl.handle.net/10033/295052
Frontiers in cellular and infection microbiology
Streptococcus pneumoniae is a leading cause of bacterial pneumonia worldwide. Given the critical role of dendritic cells (DCs) in regulating and modulating the immune response to pathogens, we investigated here the role of DCs in S. pneumoniae lung infections. Using a well-established transgenic mouse line which allows the conditional transient depletion of DCs, we showed that ablation of DCs resulted in enhanced resistance to intranasal challenge with S. pneumoniae. DCs-depleted mice exhibited delayed bacterial systemic dissemination, significantly reduced bacterial loads in the infected organs and lower levels of serum inflammatory mediators than non-depleted animals. The increased resistance of DCs-depleted mice to S. pneumoniae was associated with a better capacity to restrict pneumococci extrapulmonary dissemination. Furthermore, we demonstrated that S. pneumoniae disseminated from the lungs into the regional lymph nodes in a cell-independent manner and that this direct way of dissemination was much more efficient in the presence of DCs. We also provide evidence that S. pneumoniae induces expression and activation of matrix metalloproteinase-9 (MMP-9) in cultured bone marrow-derived DCs. MMP-9 is a protease involved in the breakdown of extracellular matrix proteins and is critical for DC trafficking across extracellular matrix and basement membranes during the migration from the periphery to the lymph nodes. MMP-9 was also significantly up-regulated in the lungs of mice after intranasal infection with S. pneumoniae. Notably, the expression levels of MMP-9 in the infected lungs were significantly decreased after depletion of DCs suggesting the involvement of DCs in MMP-9 production during pneumococcal pneumonia. Thus, we propose that S. pneumoniae can exploit the DC-derived proteolysis to open tissue barriers thereby facilitating its own dissemination from the local site of infection.
en
Archived with thanks to Frontiers in cellular and infection microbiology
Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia.
Article
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https://hzi.openrepository.com/bitstream/10033/295052/1/Rosendahl%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3045682019-08-30T11:37:44Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Kühlhorn, Franziska
author
Rath, Matthias
author
Schmoeckel, Katrin
author
Cziupka, Katharina
author
Nguyen, Huu Hung
author
Hildebrandt, Petra
author
Hünig, Thomas
author
Sparwasser, Tim
author
Huehn, Jochen
author
Pötschke, Christian
author
Bröker, Barbara M
department
Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
2013-10-24T10:19:39Z
2013
Foxp3+ regulatory T cells are required for recovery from severe sepsis. 2013, 8 (5):e65109 PLoS ONE
1932-6203
23724126
10.1371/journal.pone.0065109
http://hdl.handle.net/10033/304568
PloS one
The role of regulatory T cells (Tregs) in bacterial sepsis remains controversial because antibody-mediated depletion experiments gave conflicting results. We employed DEREG mice (DEpletion of REGulatory T cells) and a caecal ligation and puncture model to elucidate the role of CD4(+)Foxp3(+) Tregs in sepsis. In DEREG mice natural Tregs can be visualized easily and selectively depleted by diphtheria toxin because the animals express the diphtheria toxin receptor and enhanced green fluorescent protein as a fusion protein under the control of the foxp3 locus. We confirmed rapid Treg-activation and an increased ratio of Tregs to Teffs in sepsis. Nevertheless, 24 h after sepsis induction, Treg-depleted and control mice showed equally strong inflammation, immune cell immigration into the peritoneum and bacterial dissemination. During the first 36 h of disease survival was not influenced by Treg-depletion. Later, however, only Treg-competent animals recovered from the insult. We conclude that the suppressive capacity of Tregs is not sufficient to control overwhelming inflammation and early mortality, but is a prerequisite for the recovery from severe sepsis.
en
Archived with thanks to PloS one
Foxp3+ regulatory T cells are required for recovery from severe sepsis.
Article
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https://hzi.openrepository.com/bitstream/10033/304568/1/k%c3%bchlhorn%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/304568/8/k%c3%bchlhorn%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3047022019-08-30T11:37:23Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Li, Xu-Wen
author
Herrmann, Jennifer
author
Zang, Yi
author
Grellier, Philippe
author
Prado, Soizic
author
Müller, Rolf
author
Nay, Bastien
department
Muséum National d'Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, France.
2013-10-29T13:44:51Z
2013
Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues. 2013, 9:1551-8 Beilstein J Org Chem
1860-5397
23946854
10.3762/bjoc.9.176
http://hdl.handle.net/10033/304702
Beilstein journal of organic chemistry
Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad-Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure-activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.
en
Archived with thanks to Beilstein journal of organic chemistry
Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/304702/1/Li%20et%20al_final.pdf
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MD5
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URL
https://hzi.openrepository.com/bitstream/10033/304702/8/Li%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3048242019-08-30T11:37:23Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Strobel, Tina
author
Schmidt, Yvonne
author
Linnenbrink, Anton
author
Luzhetskyy, Andriy N
author
Luzhetska, Marta
author
Taguchi, Takaaki
author
Brötz, Elke
author
Paululat, Thomas
author
Stasevych, Maryna
author
Stanko, Oleg
author
Novikov, Volodymyr
author
Bechthold, Andreas
department
Albert Ludwigs University of Freiburg, Department of Pharmaceutical Biology and Biotechnology, Freiburg, Germany.
2013-10-30T15:19:00Z
2013-09
Tracking down biotransformation to the genetic level: identification of a highly flexible glycosyltransferase from Saccharothrix espanaensis. 2013, 79 (17):5224-32 Appl. Environ. Microbiol.
1098-5336
23793643
10.1128/AEM.01652-13
http://hdl.handle.net/10033/304824
Applied and environmental microbiology
Saccharothrix espanaensis is a member of the order Actinomycetales. The genome of the strain has been sequenced recently, revealing 106 glycosyltransferase genes. In this paper, we report the detection of a glycosyltransferase from Saccharothrix espanaensis which is able to rhamnosylate different phenolic compounds targeting different positions of the molecules. The gene encoding the flexible glycosyltransferase is not located close to a natural product biosynthetic gene cluster. Therefore, the native function of this enzyme might be not the biosynthesis of a secondary metabolite but the glycosylation of internal and external natural products as part of a defense mechanism.
en
Archived with thanks to Applied and environmental microbiology
Tracking down biotransformation to the genetic level: identification of a highly flexible glycosyltransferase from Saccharothrix espanaensis.
Article
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https://hzi.openrepository.com/bitstream/10033/304824/1/Strobel%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3067122019-08-30T11:26:42Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Gross, Peter C
author
Burkart, Sonja C
author
Müller, Rolf
department
Biotech Processes and Analytics Department, PharmBioTec GmbH, D-66123 Saarbrücken, Germany. Electronic address: p.gross@pharmbiotec.de.
2013-12-11T13:45:10Z
2014-01
Analytics of the therapeutic peptide aviptadil by sheathless CE-MS and comparison with nanoRP-HPLC-MS. 2014, 88:477-82 J Pharm Biomed Anal
1873-264X
24176753
10.1016/j.jpba.2013.09.024
http://hdl.handle.net/10033/306712
Journal of pharmaceutical and biomedical analysis
Purification and quality control of therapeutic peptides is often performed by one single method, RP-HPLC. As usage of an orthogonal technique is highly advisable for quality assurance, capillary electrophoresis (CE) employing a coated capillary coupled via a sheathless interface to a mass spectrometer was applied in parallel. The basic therapeutic peptide aviptadil served as a model substance to study the impurity profiles revealing 15 detectable impurities using CE-MS, two were detected by an appropriate nanoRP-HPLC-MS method. None of the impurities detected by CE were observed in LC and vice versa. The LOD in CE-MS was determined in the base peak electropherogram at ∼1fmol, a value 2500 times smaller than the LOD found in nanoRP-HPLC-MS (3pmol). In nanoRP-HPLC-MS only 0.2% of the extrapolated CE-MS signal for a 25ng aviptadil load was observed. We conclude that both, the LOD as well as the impurity profile of aviptadil, as analyzed by nanoRP-HPLC are influenced by both, the ligand-derivatized silica matrix and the flow-rate. Peptides may disappear completely and their variable emergence may lead to the determination of incorrect ratios as present in the sample.
en
Archived with thanks to Journal of pharmaceutical and biomedical analysis
Analytics of the therapeutic peptide aviptadil by sheathless CE-MS and comparison with nanoRP-HPLC-MS.
Article
Tk9OLUVYQ0xVU0lWRSBESVNUUklCVVRJT04gTElDRU5TRQoKQnkgc2lnbmluZyBhbmQgc3VibWl0dGluZyB0aGlzIGxpY2Vuc2UsIHlvdSAodGhlIGF1dGhvcihzKSBvciBjb3B5cmlnaHQKb3duZXIpIGdyYW50cyB0byBIZWxtaG9sdHogWmVudHJ1bSBm77+9ciBJbmZla3Rpb25zZm9yc2NodW5nIFJlcG9zaXRvcnkgKEhaSSkgdGhlIG5vbi1leGNsdXNpdmUgcmlnaHQgdG8gcmVwcm9kdWNlLAp0cmFuc2xhdGUgKGFzIGRlZmluZWQgYmVsb3cpLCBhbmQvb3IgZGlzdHJpYnV0ZSB5b3VyIHN1Ym1pc3Npb24gKGluY2x1ZGluZwp0aGUgYWJzdHJhY3QpIHdvcmxkd2lkZSBpbiBwcmludCBhbmQgZWxlY3Ryb25pYyBmb3JtYXQgYW5kIGluIGFueSBtZWRpdW0sCmluY2x1ZGluZyBidXQgbm90IGxpbWl0ZWQgdG8gYXVkaW8gb3IgdmlkZW8uCgpZb3UgYWdyZWUgdGhhdCBIWkkgbWF5LCB3aXRob3V0IGNoYW5naW5nIHRoZSBjb250ZW50LCB0cmFuc2xhdGUgdGhlCnN1Ym1pc3Npb24gdG8gYW55IG1lZGl1bSBvciBmb3JtYXQgZm9yIHRoZSBwdXJwb3NlIG9mIHByZXNlcnZhdGlvbi4KCllvdSBhbHNvIGFncmVlIHRoYXQgSFpJIG1heSBrZWVwIG1vcmUgdGhhbiBvbmUgY29weSBvZiB0aGlzIHN1Ym1pc3Npb24gZm9yCnB1cnBvc2VzIG9mIHNlY3VyaXR5LCBiYWNrLXVwIGFuZCBwcmVzZXJ2YXRpb24uCgpZb3UgcmVwcmVzZW50IHRoYXQgdGhlIHN1Ym1pc3Npb24gaXMgeW91ciBvcmlnaW5hbCB3b3JrLCBhbmQgdGhhdCB5b3UgaGF2ZQp0aGUgcmlnaHQgdG8gZ3JhbnQgdGhlIHJpZ2h0cyBjb250YWluZWQgaW4gdGhpcyBsaWNlbnNlLiBZb3UgYWxzbyByZXByZXNlbnQKdGhhdCB5b3VyIHN1Ym1pc3Npb24gZG9lcyBub3QsIHRvIHRoZSBiZXN0IG9mIHlvdXIga25vd2xlZGdlLCBpbmZyaW5nZSB1cG9uCmFueW9uZSdzIGNvcHlyaWdodC4KCklmIHRoZSBzdWJtaXNzaW9uIGNvbnRhaW5zIG1hdGVyaWFsIGZvciB3aGljaCB5b3UgZG8gbm90IGhvbGQgY29weXJpZ2h0LAp5b3UgcmVwcmVzZW50IHRoYXQgeW91IGhhdmUgb2J0YWluZWQgdGhlIHVucmVzdHJpY3RlZCBwZXJtaXNzaW9uIG9mIHRoZQpjb3B5cmlnaHQgb3duZXIgdG8gZ3JhbnQgSFpJIHRoZSByaWdodHMgcmVxdWlyZWQgYnkgdGhpcyBsaWNlbnNlLCBhbmQgdGhhdApzdWNoIHRoaXJkLXBhcnR5IG93bmVkIG1hdGVyaWFsIGlzIGNsZWFybHkgaWRlbnRpZmllZCBhbmQgYWNrbm93bGVkZ2VkCndpdGhpbiB0aGUgdGV4dCBvciBjb250ZW50IG9mIHRoZSBzdWJtaXNzaW9uLgoKSUYgVEhFIFNVQk1JU1NJT04gSVMgQkFTRUQgVVBPTiBXT1JLIFRIQVQgSEFTIEJFRU4gU1BPTlNPUkVEIE9SIFNVUFBPUlRFRApCWSBBTiBBR0VOQ1kgT1IgT1JHQU5JWkFUSU9OIE9USEVSIFRIQU4gSFpJLCBZT1UgUkVQUkVTRU5UIFRIQVQgWU9VIEhBVkUKRlVMRklMTEVEIEFOWSBSSUdIVCBPRiBSRVZJRVcgT1IgT1RIRVIgT0JMSUdBVElPTlMgUkVRVUlSRUQgQlkgU1VDSApDT05UUkFDVCBPUiBBR1JFRU1FTlQuCgpIWkkgd2lsbCBjbGVhcmx5IGlkZW50aWZ5IHlvdXIgbmFtZShzKSBhcyB0aGUgYXV0aG9yKHMpIG9yIG93bmVyKHMpIG9mIHRoZQpzdWJtaXNzaW9uLCBhbmQgd2lsbCBub3QgbWFrZSBhbnkgYWx0ZXJhdGlvbiwgb3RoZXIgdGhhbiBhcyBhbGxvd2VkIGJ5IHRoaXMKbGljZW5zZSwgdG8geW91ciBzdWJtaXNzaW9uLgo=
URL
https://hzi.openrepository.com/bitstream/10033/306712/1/Gross%2c%20Burkart%20and%20M%c3%bcller_final.pdf
File
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Gross, Burkart and Müller_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/306712/8/Gross%2c%20Burkart%20and%20M%c3%bcller_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3110592019-08-30T11:37:00Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Ko, Ya-Ping
author
Kuipers, Annemarie
author
Freitag, Claudia M
author
Jongerius, Ilse
author
Medina, Eva
author
van Rooijen, Willemien J
author
Spaan, András N
author
van Kessel, Kok P M
author
Höök, Magnus
author
Rooijakkers, Suzan H M
department
RG Infection immunology, Helmholtz Centre for infection research (HZI), Inhoffenstr. 7, D-38125 Braunschweig, Germany
2014-01-08T09:58:11Z
2013-12
Phagocytosis Escape by a Staphylococcus aureus Protein That Connects Complement and Coagulation Proteins at the Bacterial Surface. 2013, 9 (12):e1003816 PLoS Pathog.
1553-7374
24348255
10.1371/journal.ppat.1003816
http://hdl.handle.net/10033/311059
PLoS pathogens
Upon contact with human plasma, bacteria are rapidly recognized by the complement system that labels their surface for uptake and clearance by phagocytic cells. Staphylococcus aureus secretes the 16 kD Extracellular fibrinogen binding protein (Efb) that binds two different plasma proteins using separate domains: the Efb N-terminus binds to fibrinogen, while the C-terminus binds complement C3. In this study, we show that Efb blocks phagocytosis of S. aureus by human neutrophils. In vitro, we demonstrate that Efb blocks phagocytosis in plasma and in human whole blood. Using a mouse peritonitis model we show that Efb effectively blocks phagocytosis in vivo, either as a purified protein or when produced endogenously by S. aureus. Mutational analysis revealed that Efb requires both its fibrinogen and complement binding residues for phagocytic escape. Using confocal and transmission electron microscopy we show that Efb attracts fibrinogen to the surface of complement-labeled S. aureus generating a 'capsule'-like shield. This thick layer of fibrinogen shields both surface-bound C3b and antibodies from recognition by phagocytic receptors. This information is critical for future vaccination attempts, since opsonizing antibodies may not function in the presence of Efb. Altogether we discover that Efb from S. aureus uniquely escapes phagocytosis by forming a bridge between a complement and coagulation protein.
en
Archived with thanks to PLoS pathogens
Phagocytosis Escape by a Staphylococcus aureus Protein That Connects Complement and Coagulation Proteins at the Bacterial Surface.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/311059/1/Ko%20et%20al_final.pdf
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MD5
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URL
https://hzi.openrepository.com/bitstream/10033/311059/8/Ko%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3112022019-08-30T11:37:00Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Horst, Sarah A
author
Linnér, Anna
author
Beineke, Andreas
author
Lehne, Sabine
author
Höltje, Claudia
author
Hecht, Alexander
author
Norrby-Teglund, Anna
author
Medina, Eva
department
Dep. of infection immunology, Helmholtz Centre for infection research, Braunschweig, Germany
2014-01-10T10:33:53Z
2013
Prognostic value and therapeutic potential of TREM-1 in Streptococcus pyogenes- induced sepsis. 2013, 5 (6):581-90 J Innate Immun
1662-8128
23571837
10.1159/000348283
http://hdl.handle.net/10033/311202
Journal of innate immunity
TREM-1 (triggering receptor expressed on myeloid cells) is a surface molecule expressed on neutrophils and macrophages which has been implicated in the amplification of inflammatory responses triggered during infection. In the present study, we have investigated the clinical significance of TREM-1 in Streptococcus pyogenes-induced severe sepsis in both experimentally infected mice as well as in patients with streptococcal toxic shock. We found that S. pyogenes induced a dose-dependent upregulation of TREM-1 in in vitro cultured phagocytic cells and in the organs of S. pyogenes-infected mice. Furthermore, we reported a positive correlation between serum levels of soluble TREM-1 (sTREM-1) and disease severity in infected patients as well as in experimentally infected mice. Hence, sTREM-1 may represent a useful surrogate marker for streptococcal sepsis. We found that modulation of TREM-1 by administration of the TREM-1 decoy receptor rTREM-1/Fc substantially attenuated the synthesis of inflammatory cytokines. More importantly, treatment of S. pyogenes-infected septic mice with rTREM-1/Fc or the synthetically produced conserved extracellular domain LP17 significantly improved disease outcome. In summary, our data suggest that TREM-1 may not only represent a valuable marker for S. pyogenes infection severity but it may also be an attractive target for the treatment of streptococcal sepsis.
en
Archived with thanks to Journal of innate immunity
Prognostic value and therapeutic potential of TREM-1 in Streptococcus pyogenes- induced sepsis.
Article
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https://hzi.openrepository.com/bitstream/10033/311202/1/Horst%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3261942019-08-30T11:30:58Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Horbal, Liliya
author
Rebets, Yuriy
author
Rabyk, Mariya
author
Makitrynskyy, Roman
author
Luzhetskyy, Andriy N
author
Fedorenko, Victor
author
Bechthold, Andreas
2014-09-17T11:36:55Z
2012
SimReg1 is a master switch for biosynthesis and export of simocyclinone D8 and its precursors. 2012, 2 (1):1 AMB Express
2191-0855
22214346
10.1186/2191-0855-2-1
http://hdl.handle.net/10033/326194
AMB Express
Analysis of the simocyclinone biosynthesis (sim) gene cluster of Streptomyces antibioticus Tü6040 led to the identification of a putative pathway specific regulatory gene simReg1. In silico analysis places the SimReg1 protein in the OmpR-PhoB subfamily of response regulators. Gene replacement of simReg1 from the S. antibioticus chromosome completely abolishes simocyclinone production indicating that SimReg1 is a key regulator of simocyclinone biosynthesis. Results of the DNA-shift assays and reporter gene expression analysis are consistent with the idea that SimReg1 activates transcription of simocyclinone biosynthesis, transporter genes, regulatory gene simReg3 and his own transcription. The presence of extracts (simocyclinone) from S. antibioticus Tü6040 × pSSimR1-1 could dissociate SimReg1 from promoter regions. A preliminary model for regulation of simocyclinone biosynthesis and export is discussed.
en
Archived with thanks to AMB Express
SimReg1 is a master switch for biosynthesis and export of simocyclinone D8 and its precursors.
Article
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
URL
https://hzi.openrepository.com/bitstream/10033/326194/1/Horbal%20et%20al_final.pdf
File
MD5
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URL
https://hzi.openrepository.com/bitstream/10033/326194/8/Horbal%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3326032019-08-30T11:35:39Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Foerster, F
author
Braig, S
author
Moser, C
author
Kubisch, R
author
Busse, J
author
Wagner, E
author
Schmoeckel, E
author
Mayr, D
author
Schmitt, S
author
Huettel, S
author
Zischka, H
author
Mueller, R
author
Vollmar, A M
2014-10-09T14:01:36Z
2014
Targeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ. 2014, 5:e1398 Cell Death Dis
2041-4889
25165884
10.1038/cddis.2014.363
http://hdl.handle.net/10033/332603
Cell death & disease
Targeting the actin cytoskeleton (CSK) of cancer cells offers a valuable strategy in cancer therapy. There are a number of natural compounds that interfere with the actin CSK, but the mode of their cytotoxic action and, moreover, their tumor-specific mechanisms are quite elusive. We used the myxobacterial compound Chondramide as a tool to first elucidate the mechanisms of cytotoxicity of actin targeting in breast cancer cells (MCF7, MDA-MB-231). Chondramide inhibits cellular actin filament dynamics shown by a fluorescence-based analysis (fluorescence recovery after photobleaching (FRAP)) and leads to apoptosis characterized by phosphatidylserine exposure, release of cytochrome C from mitochondria and finally activation of caspases. Chondramide enhances the occurrence of mitochondrial permeability transition (MPT) by affecting known MPT modulators: Hexokinase II bound to the voltage-dependent anion channel (VDAC) translocated from the outer mitochondrial membrane to the cytosol and the proapoptotic protein Bad were recruited to the mitochondria. Importantly, protein kinase C-ɛ (PKCɛ), a prosurvival kinase possessing an actin-binding site and known to regulate the hexokinase/VDAC interaction as well as Bad phosphorylation was identified as the link between actin CSK and apoptosis induction. PKCɛ, which was found overexpressed in breast cancer cells, accumulated in actin bundles induced by Chondramide and lost its activity. Our second goal was to characterize the potential tumor-specific action of actin-binding agents. As the nontumor breast epithelial cell line MCF-10A in fact shows resistance to Chondramide-induced apoptosis and notably express low level of PKCɛ, we suggest that trapping PKCɛ via Chondramide-induced actin hyperpolymerization displays tumor cell specificity. Our work provides a link between targeting the ubiquitously occurring actin CSK and selective inhibition of pro-tumorigenic PKCɛ, thus setting the stage for actin-stabilizing agents as innovative cancer drugs. This is moreover supported by the in vivo efficacy of Chondramide triggered by abrogation of PKCɛ signaling shown in a xenograft breast cancer model.
en
Archived with thanks to Cell death & disease
Targeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ.
Article
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
URL
https://hzi.openrepository.com/bitstream/10033/332603/1/Foerster%20et%20al_final.pdf
File
MD5
3c013b33a17314a55115de2ee0232a51
3619343
application/pdf
Foerster et al_final.pdf
URL
https://hzi.openrepository.com/bitstream/10033/332603/8/Foerster%20et%20al_final.pdf.txt
File
MD5
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Foerster et al_final.pdf.txt
oai:repository.helmholtz-hzi.de:10033/3328032019-08-30T11:35:39Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Kessler, Sonja M
author
Simon, Yvette
author
Gemperlein, Katja
author
Gianmoena, Kathrin
author
Cadenas, Cristina
author
Zimmer, Vincent
author
Pokorny, Juliane
author
Barghash, Ahmad
author
Helms, Volkhard
author
van Rooijen, Nico
author
Bohle, Rainer M
author
Lammert, Frank
author
Hengstler, Jan G
author
Mueller, Rolf
author
Haybaeck, Johannes
author
Kiemer, Alexandra K
2014-10-15T13:13:54Z
2014
Fatty acid elongation in non-alcoholic steatohepatitis and hepatocellular carcinoma. 2014, 15 (4):5762-73 Int J Mol Sci
1422-0067
24714086
10.3390/ijms15045762
http://hdl.handle.net/10033/332803
International journal of molecular sciences
Non-alcoholic steatohepatitis (NASH) represents a risk factor for the development of hepatocellular carcinoma (HCC) and is characterized by quantitative and qualitative changes in hepatic lipids. Since elongation of fatty acids from C16 to C18 has recently been reported to promote both hepatic lipid accumulation and inflammation we aimed to investigate whether a frequently used mouse NASH model reflects this clinically relevant feature and whether C16 to C18 elongation can be observed in HCC development. Feeding mice a methionine and choline deficient diet to model NASH not only increased total hepatic fatty acids and cholesterol, but also distinctly elevated the C18/C16 ratio, which was not changed in a model of simple steatosis (ob/ob mice). Depletion of Kupffer cells abrogated both quantitative and qualitative methionine-and-choline deficient (MCD)-induced alterations in hepatic lipids. Interestingly, mimicking inflammatory events in early hepatocarcinogenesis by diethylnitrosamine-induced carcinogenesis (48 h) increased hepatic lipids and the C18/C16 ratio. Analyses of human liver samples from patients with NASH or NASH-related HCC showed an elevated expression of the elongase ELOVL6, which is responsible for the elongation of C16 fatty acids. Taken together, our findings suggest a detrimental role of an altered fatty acid pattern in the progression of NASH-related liver disease.
en
Archived with thanks to International journal of molecular sciences
Fatty acid elongation in non-alcoholic steatohepatitis and hepatocellular carcinoma.
Article
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oai:repository.helmholtz-hzi.de:10033/3328552019-08-30T11:27:16Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Loof, Torsten G
author
Deicke, Christin
author
Medina, Eva
department
Helmholtz Centre for infection research, Inhoffenstr. 7, D38124 Braunschweig, Germany.
2014-10-17T09:01:15Z
2014
The role of coagulation/fibrinolysis during Streptococcus pyogenes infection. 2014, 4:128 Front Cell Infect Microbiol
2235-2988
25309880
10.3389/fcimb.2014.00128
http://hdl.handle.net/10033/332855
Frontiers in cellular and infection microbiology
The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis and is a host defense mechanism that protects the integrity of the vascular system after tissue injury. During bacterial infections, the coagulation system cooperates with the inflammatory system to eliminate the invading pathogens. However, pathogenic bacteria have frequently evolved mechanisms to exploit the hemostatic system components for their own benefit. Streptococcus pyogenes, also known as Group A Streptococcus, provides a remarkable example of the extraordinary capacity of pathogens to exploit the host hemostatic system to support microbial survival and dissemination. The coagulation cascade comprises the contact system (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway), both leading to fibrin formation. During the early phase of S. pyogenes infection, the activation of the contact system eventually leads to bacterial entrapment within a fibrin clot, where S. pyogenes is immobilized and killed. However, entrapped S. pyogenes can circumvent the antimicrobial effect of the clot by sequestering host plasminogen on the bacterial cell surface that, after conversion into its active proteolytic form, plasmin, degrades the fibrin network and facilitates the liberation of S. pyogenes from the clot. Furthermore, the surface-localized fibrinolytic activity also cleaves a variety of extracellular matrix proteins, thereby enabling S. pyogenes to migrate across barriers and disseminate within the host. This review summarizes the knowledge gained during the last two decades on the role of coagulation/fibrinolysis in host defense against S. pyogenes as well as the strategies developed by this pathogen to evade and exploit these host mechanisms for its own benefit.
Archived with thanks to Frontiers in cellular and infection microbiology
The role of coagulation/fibrinolysis during Streptococcus pyogenes infection.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/332855/1/Loof%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/3349112019-08-30T11:35:39Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Kolinko, Isabel
author
Lohße, Anna
author
Borg, Sarah
author
Raschdorf, Oliver
author
Jogler, Christian
author
Tu, Qiang
author
Pósfai, Mihály
author
Tompa, Eva
author
Plitzko, Jürgen M
author
Brachmann, Andreas
author
Wanner, Gerhard
author
Müller, Rolf
author
Zhang, Youming
author
Schüler, Dirk
department
Ludwig-Maximilians-Universität München, Department of Biology I, Großhaderner Straße 2-4, 82152 Martinsried, Germany.
2014-11-14T14:02:12Z
2014-03
Biosynthesis of magnetic nanostructures in a foreign organism by transfer of bacterial magnetosome gene clusters. 2014, 9 (3):193-7 Nat Nanotechnol
1748-3395
24561353
10.1038/nnano.2014.13
http://hdl.handle.net/10033/334911
Nature nanotechnology
The synthetic production of monodisperse single magnetic domain nanoparticles at ambient temperature is challenging. In nature, magnetosomes--membrane-bound magnetic nanocrystals with unprecedented magnetic properties--can be biomineralized by magnetotactic bacteria. However, these microbes are difficult to handle. Expression of the underlying biosynthetic pathway from these fastidious microorganisms within other organisms could therefore greatly expand their nanotechnological and biomedical applications. So far, this has been hindered by the structural and genetic complexity of the magnetosome organelle and insufficient knowledge of the biosynthetic functions involved. Here, we show that the ability to biomineralize highly ordered magnetic nanostructures can be transferred to a foreign recipient. Expression of a minimal set of genes from the magnetotactic bacterium Magnetospirillum gryphiswaldense resulted in magnetosome biosynthesis within the photosynthetic model organism Rhodospirillum rubrum. Our findings will enable the sustainable production of tailored magnetic nanostructures in biotechnologically relevant hosts and represent a step towards the endogenous magnetization of various organisms by synthetic biology.
en
Biosynthesis of magnetic nanostructures in a foreign organism by transfer of bacterial magnetosome gene clusters.
Article
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oai:repository.helmholtz-hzi.de:10033/3384892019-08-30T11:35:39Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Held, Jana
author
Gebru, Tamirat
author
Kalesse, Markus
author
Jansen, Rolf
author
Gerth, Klaus
author
Müller, Rolf
author
Mordmüller, Benjamin
2015-01-16T14:40:57Z
2014-11
Antimalarial activity of the myxobacterial macrolide chlorotonil a. 2014, 58 (11):6378-84 Antimicrob. Agents Chemother.
1098-6596
25114138
10.1128/AAC.03326-14
http://hdl.handle.net/10033/338489
Antimicrobial agents and chemotherapy
Myxobacteria are Gram-negative soil-dwelling bacteria belonging to the phylum Proteobacteria. They are a rich source of promising compounds for clinical application, such as epothilones for cancer therapy and several new antibiotics. In the course of a bioactivity screening program of secondary metabolites produced by Sorangium cellulosum strains, the macrolide chlorotonil A was found to exhibit promising antimalarial activity. Subsequently, we evaluated chlorotonil A against Plasmodium falciparum laboratory strains and clinical isolates from Gabon. Chlorotonil A was highly active, with a 50% inhibitory concentration between 4 and 32 nM; additionally, no correlations between the activities of chlorotonil A and artesunate (rho, 0.208) or chloroquine (rho, -0.046) were observed. Per os treatment of Plasmodium berghei-infected mice with four doses of as little as 36 mg of chlorotonil A per kg of body weight led to the suppression of parasitemia with no obvious signs of toxicity. Chlorotonil A acts against all stages of intraerythrocytic parasite development, including ring-stage parasites and stage IV to V gametocytes, and it requires only a very short exposure to the parasite to exert its antimalarial action. Conclusively, chlorotonil A has an exceptional and unprecedented profile of action and represents an urgently required novel antimalarial chemical scaffold. Therefore, we propose it as a lead structure for further development as an antimalarial chemotherapeutic.
en
Antimalarial activity of the myxobacterial macrolide chlorotonil a.
Article
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oai:repository.helmholtz-hzi.de:10033/3443442019-08-30T11:37:23Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Simon, Yvette
author
Kessler, Sonja M
author
Gemperlein, Katja
author
Bohle, Rainer M
author
Müller, Rolf
author
Haybaeck, Johannes
author
Kiemer, Alexandra K
department
Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66123 Saarbrücken, Germany.
2015-02-10T14:50:58Z
2014-12-21
Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis. 2014, 20 (47):17839-50 World J. Gastroenterol.
2219-2840
25548482
10.3748/wjg.v20.i47.17839
http://hdl.handle.net/10033/344344
World journal of gastroenterology : WJG
To characterize how insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol.
en
Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/3443862019-08-30T11:37:44Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Garcia, Ronald
author
Pistorius, Dominik
author
Stadler, Marc
author
Müller, Rolf
2015-02-12T13:47:04Z
2011-04
Fatty acid-related phylogeny of myxobacteria as an approach to discover polyunsaturated omega-3/6 Fatty acids. 2011, 193 (8):1930-42 J. Bacteriol.
1098-5530
21317327
10.1128/JB.01091-10
http://hdl.handle.net/10033/344386
Journal of bacteriology
In an analysis of 47 aerobic myxobacterial strains, representing 19 genera in suborders Cystobacterineae, Nannocystineae, Sorangiineae, and a novel isolate, "Aetherobacter" SBSr008, an enormously diverse array of fatty acids (FAs) was found. The distribution of straight-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) supports the reported clustering of strains in the phylogenetic tree based on 16S rRNA genes. This finding additionally allows the prediction and assignment of the novel isolate SBSr008 into its corresponding taxon. Sorangiineae predominantly contains larger amounts of SCFA (57 to 84%) than BCFA. On the other hand, Cystobacterineae exhibit significant BCFA content (53 to 90%), with the exception of the genus Stigmatella. In Nannocystineae, the ratio of BCFA and SCFA seems dependent on the taxonomic clade. Myxobacteria could also be identified and classified by using their specific and predominant FAs as biomarkers. Nannocystineae is remarkably unique among the suborders for its absence of hydroxy FAs. After the identification of arachidonic (AA) FA in Phaselicystidaceae, eight additional polyunsaturated fatty acids (PUFAs) belonging to the omega-6 and omega-3 families were discovered. Here we present a comprehensive report of FAs found in aerobic myxobacteria. Gliding bacteria belonging to Flexibacter and Herpetosiphon were chosen for comparative analysis to determine their FA profiles in relation to the myxobacteria.
en
Fatty acid-related phylogeny of myxobacteria as an approach to discover polyunsaturated omega-3/6 Fatty acids.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/3454072019-08-30T11:31:23Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Khatri, Yogan
author
Hannemann, Frank
author
Perlova, Olena
author
Müller, Rolf
author
Bernhardt, Rita
2015-02-26T12:43:15Z
2011-06-06
Investigation of cytochromes P450 in myxobacteria: excavation of cytochromes P450 from the genome of Sorangium cellulosum So ce56. 2011, 585 (11):1506-13 FEBS Lett.
1873-3468
21521637
10.1016/j.febslet.2011.04.035
http://hdl.handle.net/10033/345407
FEBS letters
The exploitation of cytochromes P450 for novel biotechnological application and for the investigation of their physiological function is of great scientific interest in this post genomic era, where an extraordinary biodiversity of P450 genes has been derived from all forms of life. The study of P450s in the myxobacterium Sorangium cellulosum strain So ce56, the producer of novel secondary metabolites of pharmaceutical interest is the research topic, in which we were engaged since the beginning of its genome sequencing project. We herein disclosed the cytochrome P450 complements (CYPomes) of spore-forming myxobacterial species, Stigmatella aurantiaca DW4/3-1, Haliangium ochraceum DSM 14365 and Myxococcus xanthus DK1622, and their potential pharmaceutical significance has been discussed.
en
Investigation of cytochromes P450 in myxobacteria: excavation of cytochromes P450 from the genome of Sorangium cellulosum So ce56.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/345407/1/khatri%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3461552019-08-30T11:30:58Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Scherer, Olga
author
Steinmetz, Heinrich
author
Kaether, Christoph
author
Weinigel, Christina
author
Barz, Dagmar
author
Kleinert, Hartmut
author
Menche, Dirk
author
Müller, Rolf
author
Pergola, Carlo
author
Werz, Oliver
department
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C23, D-66123 Saarbrücken, Germany.
2015-03-04T13:31:11Z
2014-10-15
Targeting V-ATPase in primary human monocytes by archazolid potently represses the classical secretion of cytokines due to accumulation at the endoplasmic reticulum. 2014, 91 (4):490-500 Biochem. Pharmacol.
1873-2968
25107704
10.1016/j.bcp.2014.07.028
http://hdl.handle.net/10033/346155
Biochemical pharmacology
The macrolide archazolid inhibits vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, and potently suppresses cancer cell growth at low nanomolar concentrations. In view of the growing link between inflammation and cancer, we investigated whether inhibition of V-ATPase by archazolid may affect primary human monocytes that can promote cancer by sustaining inflammation through the release of tumor-promoting cytokines. Human primary monocytes express V-ATPase, and archazolid (10-100nM) increases the vesicular pH in these cells. Archazolid (10nM) markedly reduced the release of pro-inflammatory (TNF-α, interleukin-6 and -8) but also of anti-inflammatory (interleukin-10) cytokines in monocytes stimulated with LPS, without affecting cell viability up to 1000nM. Of interest, secretion of interleukin-1β was increased by archazolid. Comparable effects were obtained by the V-ATPase inhibitors bafilomycin and apicularen. The phosphorylation of p38 MAPK and ERK-1/2, Akt, SAPK/JNK or of the inhibitor of NFκB (IκBα) as well as mRNA expression of IL-8 were not altered by archazolid in LPS-stimulated monocytes. Instead, archazolid caused endoplasmic reticulum (ER) stress response visualized by increased BiP expression and accumulation of IL-8 (and TNF-α) at the ER, indicating a perturbation of protein secretion. In conclusion, by interference with V-ATPase, archazolid significantly affects the secretion of cytokines due to accumulation at the ER which might be of relevance when using these agents for cancer therapy.
en
Targeting V-ATPase in primary human monocytes by archazolid potently represses the classical secretion of cytokines due to accumulation at the endoplasmic reticulum.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/346155/1/Scherer%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3461992019-08-30T11:30:58Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Sours, Kevin M
author
Xiao, Yao
author
Ahn, Natalie G
department
Helmholtz Institute for Pharmaceutical Research, Saarland University, Saarbrücken, Germany.
2015-03-05T10:54:39Z
2014-05-01
Extracellular-regulated kinase 2 is activated by the enhancement of hinge flexibility. 2014, 426 (9):1925-35 J. Mol. Biol.
1089-8638
24534729
10.1016/j.jmb.2014.02.011
http://hdl.handle.net/10033/346199
Journal of molecular biology
Protein motions underlie conformational and entropic contributions to enzyme catalysis; however, relatively little is known about the ways in which this occurs. Studies of the mitogen-activated protein kinase ERK2 (extracellular-regulated protein kinase 2) by hydrogen-exchange mass spectrometry suggest that activation enhances backbone flexibility at the linker between N- and C-terminal domains while altering nucleotide binding mode. Here, we address the hypothesis that enhanced backbone flexibility within the hinge region facilitates kinase activation. We show that hinge mutations enhancing flexibility promote changes in the nucleotide binding mode consistent with domain movement, without requiring phosphorylation. They also lead to the activation of monophosphorylated ERK2, a form that is normally inactive. The hinge mutations bypass the need for pTyr but not pThr, suggesting that Tyr phosphorylation controls hinge motions. In agreement, monophosphorylation of pTyr enhances both hinge flexibility and nucleotide binding mode, measured by hydrogen-exchange mass spectrometry. Our findings demonstrate that regulated protein motions underlie kinase activation. Our working model is that constraints to domain movement in ERK2 are overcome by phosphorylation at pTyr, which increases hinge dynamics to promote the active conformation of the catalytic site.
en
Extracellular-regulated kinase 2 is activated by the enhancement of hinge flexibility.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/346199/1/Sours%20et%20al_final.pdf
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https://hzi.openrepository.com/bitstream/10033/346199/2/Sours%20et%20al_ERK2%20activated%20by%20hinge%20regulation_Suppl%20%20JMB_2014.pdf
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Sours et al_ERK2 activated by hinge regulation_Suppl JMB_2014.pdf
URL
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URL
https://hzi.openrepository.com/bitstream/10033/346199/12/Sours%20et%20al_ERK2%20activated%20by%20hinge%20regulation_Suppl%20%20JMB_2014.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/3468782019-08-30T11:26:13Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Tuchscherr, Lorena
author
Medina, Eva
author
Hussain, Muzaffar
author
Völker, Wolfgang
author
Heitmann, Vanessa
author
Niemann, Silke
author
Holzinger, Dirk
author
Roth, Johannes
author
Proctor, Richard A
author
Becker, Karsten
author
Peters, Georg
author
Löffler, Bettina
2015-03-19T09:21:47Z
2011-03
Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. 2011, 3 (3):129-41 EMBO Mol Med
1757-4684
21268281
10.1002/emmm.201000115
http://hdl.handle.net/10033/346878
EMBO molecular medicine
Staphylococcus aureus is a frequent cause for serious, chronic and therapy-refractive infections in spite of susceptibility to antibiotics in vitro. In chronic infections, altered bacterial phenotypes, such as small colony variants (SCVs), have been found. Yet, it is largely unclear whether the ability to interconvert from the wild-type to the SCV phenotype is only a rare clinical and/or just laboratory phenomenon or is essential to sustain an infection. Here, we performed different long-term in vitro and in vivo infection models with S. aureus and we show that viable bacteria can persist within host cells and/or tissues for several weeks. Persistence induced bacterial phenotypic diversity, including SCV phenotypes, accompanied by changes in virulence factor expression and auxotrophism. However, the recovered SCV phenotypes were highly dynamic and rapidly reverted to the fully virulent wild-type form when leaving the intracellular location and infecting new cells. Our findings demonstrate that bacterial phenotype switching is an integral part of the infection process that enables the bacteria to hide inside host cells, which can be a reservoir for chronic and therapy-refractive infections.
en
Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/346878/1/tuchscherr%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/3468722019-08-30T11:37:44Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Rachid, Shwan
author
Huo, Liujie
author
Herrmann, Jennifer
author
Stadler, Marc
author
Köpcke, Bärbel
author
Bitzer, Jens
author
Müller, Rolf
2015-03-19T12:45:32Z
2011-04-11
Mining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors. 2011, 12 (6):922-31 Chembiochem
1439-7633
21387511
10.1002/cbic.201100024
http://hdl.handle.net/10033/346872
Chembiochem : a European journal of chemical biology
The cinnabaramides and salinosporamides are mixed PKS/NRPS natural products isolated from a terrestrial streptomycete and a marine actinomycete, respectively. They interfere with the proteasome and thus potentially inhibit the growth of cancer cells. The compounds exhibit a γ-lactam-β-lactone bicyclic ring structure attached to a cyclohexenyl unit and a PKS side chain. As a first step towards improving anticancer activity and permitting genetic approaches to novel analogues, we have cloned and characterized the cinnabaramide biosynthetic genes from Streptomyces sp. JS360. In addition to the expected PKS and NRPS genes, the cluster encodes functionalities for the assembly of the hexyl side chain precursor. The corresponding enzymes exhibit relaxed substrate specificities towards a number of synthesized precursors, enabling production of novel chlorinated cinnabaramides. These were isolated and analyzed for activity, revealing that derivatives bearing a chlorine atom in the PKS side chain show higher inhibitory potentials towards the proteasome's proteolytic subunits (especially the trypsin and chymotrypsin units) and higher cytotoxicities towards human tumor cell lines than the parent cinnabaramide A. Although their activities towards the proteasome were weaker than that of salinosporamide A, the cinnabaramides were found to inhibit the growth of various fungi with greater potency.
en
Mining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/346872/1/rachid%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/3468962019-08-30T11:32:16Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Proschak, Anna
author
Schultz, Katharina
author
Herrmann, Jennifer
author
Dowling, Andrea J
author
Brachmann, Alexander O
author
ffrench-Constant, Richard
author
Müller, Rolf
author
Bode, Helge B
2015-03-19T12:58:36Z
2011-09-05
Cytotoxic fatty acid amides from Xenorhabdus. 2011, 12 (13):2011-5 Chembiochem
1439-7633
21751325
10.1002/cbic.201100223
http://hdl.handle.net/10033/346896
Chembiochem : a European journal of chemical biology
en
Cytotoxic fatty acid amides from Xenorhabdus.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/346896/1/proschak%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/5285702019-08-30T11:25:43Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Menhofer, Magdalena H
author
Kubisch, Rebekka
author
Schreiner, Laura
author
Zorn, Matthias
author
Foerster, Florian
author
Mueller, Rolf
author
Raedler, Joachim O
author
Wagner, Ernst
author
Vollmar, Angelika M
author
Zahler, Stefan
department
Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbru ¨ cken, Germany.
2015-04-13T12:56:41Z
2014
The actin targeting compound Chondramide inhibits breast cancer metastasis via reduction of cellular contractility. 2014, 9 (11):e112542 PLoS ONE
1932-6203
25391145
10.1371/journal.pone.0112542
http://hdl.handle.net/10033/528570
PloS one
A major player in the process of metastasis is the actin cytoskeleton as it forms key structures in both invasion mechanisms, mesenchymal and amoeboid migration. We tested the actin binding compound Chondramide as potential anti-metastatic agent.
en
The actin targeting compound Chondramide inhibits breast cancer metastasis via reduction of cellular contractility.
Article
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oai:repository.helmholtz-hzi.de:10033/5554752019-08-30T11:26:13Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Weber, Tilmann
author
Blin, Kai
author
Duddela, Srikanth
author
Krug, Daniel
author
Kim, Hyun Uk
author
Bruccoleri, Robert
author
Lee, Sang Yup
author
Fischbach, Michael A
author
Müller, Rolf
author
Wohlleben, Wolfgang
author
Breitling, Rainer
author
Takano, Eriko
author
Medema, Marnix H
department
Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, Saarland University, Saarbrucken, Germany.
2015-05-22T14:32:00Z
2015-05-06
antiSMASH 3.0-a comprehensive resource for the genome mining of biosynthetic gene clusters. 2015: Nucleic Acids Res.
1362-4962
25948579
10.1093/nar/gkv437
http://hdl.handle.net/10033/555475
Nucleic acids research
Microbial secondary metabolism constitutes a rich source of antibiotics, chemotherapeutics, insecticides and other high-value chemicals. Genome mining of gene clusters that encode the biosynthetic pathways for these metabolites has become a key methodology for novel compound discovery. In 2011, we introduced antiSMASH, a web server and stand-alone tool for the automatic genomic identification and analysis of biosynthetic gene clusters, available at http://antismash.secondarymetabolites.org. Here, we present version 3.0 of antiSMASH, which has undergone major improvements. A full integration of the recently published ClusterFinder algorithm now allows using this probabilistic algorithm to detect putative gene clusters of unknown types. Also, a new dereplication variant of the ClusterBlast module now identifies similarities of identified clusters to any of 1172 clusters with known end products. At the enzyme level, active sites of key biosynthetic enzymes are now pinpointed through a curated pattern-matching procedure and Enzyme Commission numbers are assigned to functionally classify all enzyme-coding genes. Additionally, chemical structure prediction has been improved by incorporating polyketide reduction states. Finally, in order for users to be able to organize and analyze multiple antiSMASH outputs in a private setting, a new XML output module allows offline editing of antiSMASH annotations within the Geneious software.
antiSMASH 3.0-a comprehensive resource for the genome mining of biosynthetic gene clusters.
Article
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oai:repository.helmholtz-hzi.de:10033/5759292019-08-30T11:28:24Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Szafranska, Anna K
author
Oxley, Andrew P A
author
Chaves-Moreno, Diego
author
Horst, Sarah A
author
Roßlenbroich, Steffen
author
Peters, Georg
author
Goldmann, Oliver
author
Rohde, Manfred
author
Sinha, Bhanu
author
Pieper, Dietmar H
author
Löffler, Bettina
author
Jauregui, Ruy
author
Wos-Oxley, Melissa L
author
Medina, Eva
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2015-08-25T12:44:17Z
2014
High-resolution transcriptomic analysis of the adaptive response of Staphylococcus aureus during acute and chronic phases of osteomyelitis. 2014, 5 (6): MBio
2150-7511
25538190
10.1128/mBio.01775-14
http://hdl.handle.net/10033/575929
mBio
Osteomyelitis is a difficult-to-eradicate bone infection typically caused by Staphylococcus aureus. In this study, we investigated the in vivo transcriptional adaptation of S. aureus during bone infection. To this end, we determined the transcriptome of S. aureus during the acute (day 7) and chronic (day 28) phases of experimental murine osteomyelitis using RNA sequencing (RNA-Seq). We identified a total of 180 genes significantly more highly expressed by S. aureus during acute or chronic in vivo infection than under in vitro growth conditions. These genes encoded proteins involved in gluconeogenesis, proteolysis of host proteins, iron acquisition, evasion of host immune defenses, and stress responses. At the regulatory level, sarA and -R and saeR and -S as well as the small RNA RsaC were predominantly expressed by S. aureus during in vivo infection. Only nine genes, including the genes encoding the arginine deiminase (ADI) pathway and those involved in the stringent response, were significantly more highly expressed by S. aureus during the chronic than the acute stage of infection. Analysis by quantitative reverse transcription-PCR (qRT-PCR) of a subset of these in vivo-expressed genes in clinical specimens yielded the same results as those observed in the murine system. Collectively, our results show that during acute osteomyelitis, S. aureus induced the transcription of genes that mediate metabolic adaptation, immune evasion, and replication. During the chronic phase, however, S. aureus switched its transcriptional response from a proliferative to a persistence mode, probably driven by the severe deficiency in nutrient supplies. Interfering with the survival strategies of S. aureus during chronic infection could lead to more effective treatments.
en
High-resolution transcriptomic analysis of the adaptive response of Staphylococcus aureus during acute and chronic phases of osteomyelitis.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/575929/1/Szafranska%20et%20al_final.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/575929/8/Szafranska%20et%20al_final.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/6210462019-08-30T11:33:30Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Lushchyk, Igor
author
Rückert, Christian
author
Zaburannyi, Nestor
author
Bechthold, Andreas
author
Kalinowski, Jörn
author
Luzhetskyy, Andriy N
2017-08-04T09:04:35Z
2014-10-10
BMC Genomics. 2014 Oct 10;15(1):885
http://dx.doi.org/10.1186/1471-2164-15-885
Abstract Background Kutzneria is a representative of a rarely observed genus of the family Pseudonocardiaceae. Kutzneria species were initially placed in the Streptosporangiaceae genus and later reconsidered to be an independent genus of the Pseudonocardiaceae. Kutzneria albida is one of the eight known members of the genus. This strain is a unique producer of the glycosylated polyole macrolide aculeximycin which is active against both bacteria and fungi. Kutzneria albida genome sequencing and analysis allow a deeper understanding of evolution of this genus of Pseudonocardiaceae, provide new insight in the phylogeny of the genus, as well as decipher the hidden secondary metabolic potential of these rare actinobacteria. Results To explore the biosynthetic potential of Kutzneria albida to its full extent, the complete genome was sequenced. With a size of 9,874,926 bp, coding for 8,822 genes, it stands alongside other Pseudonocardiaceae with large circular genomes. Genome analysis revealed 46 gene clusters potentially encoding secondary metabolite biosynthesis pathways. Two large genomic islands were identified, containing regions most enriched with secondary metabolism gene clusters. Large parts of this secondary metabolism “clustome” are dedicated to siderophores production. Conclusions Kutzneria albida is the first species of the genus Kutzneria with a completely sequenced genome. Genome sequencing allowed identifying the gene cluster responsible for the biosynthesis of aculeximycin, one of the largest known oligosaccharide-macrolide antibiotics. Moreover, the genome revealed 45 additional putative secondary metabolite gene clusters, suggesting a huge biosynthetic potential, which makes Kutzneria albida a very rich source of natural products. Comparison of the Kutzneria albida genome to genomes of other actinobacteria clearly shows its close relations with Pseudonocardiaceae in line with the taxonomic position of the genus.
en
Complete genome sequence of producer of the glycopeptide antibiotic Aculeximycin Kutzneria albida DSM 43870T, a representative of minor genus of Pseudonocardiaceae
Journal Article
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oai:repository.helmholtz-hzi.de:10033/6207782019-08-30T11:25:43Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Zaburannyi, Nestor
author
Rabyk, Mariia
author
Ostash, Bohdan
author
Fedorenko, Victor
author
Luzhetskyy, Andriy N
2017-01-27T10:45:08Z
2014-02-05
BMC Genomics. 2014 Feb 05;15(1):97
http://dx.doi.org/10.1186/1471-2164-15-97
Abstract Background The Streptomyces albus J1074 strain is one of the most widely used chassis for the heterologous production of bioactive natural products. The fast growth and an efficient genetic system make this strain an attractive model for expressing cryptic biosynthetic pathways to aid drug discovery. Results To improve its capabilities for the heterologous expression of biosynthetic gene clusters, the complete genomic sequence of S. albus J1074 was obtained. With a size of 6,841,649 bp, coding for 5,832 genes, its genome is the smallest within the genus streptomycetes. Genome analysis revealed a strong tendency to reduce the number of genetic duplicates. The whole transcriptomes were sequenced at different time points to identify the early metabolic switch from the exponential to the stationary phase in S. albus J1074. Conclusions S. albus J1074 carries the smallest genome among the completely sequenced species of the genus Streptomyces. The detailed genome and transcriptome analysis discloses its capability to serve as a premium host for the heterologous production of natural products. Moreover, the genome revealed 22 additional putative secondary metabolite gene clusters that reinforce the strain’s potential for natural product synthesis.
en
Insights into naturally minimised Streptomyces albus J1074 genome
Journal Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6207662019-08-30T11:31:23Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Perlova, Olena
author
Gerth, Klaus
author
Kuhlmann, Silvia
author
Zhang, Youming
author
Müller, Rolf
2017-01-27T09:44:51Z
2009-01-06
Microbial Cell Factories. 2009 Jan 06;8(1):1
http://dx.doi.org/10.1186/1475-2859-8-1
Abstract Although many secondary metabolites with diverse biological activities have been isolated from myxobacteria, most strains of these biotechnologically important gliding prokaryotes remain difficult to handle genetically. In this study we describe the new fast growing myxobacterial thermophilic isolate GT-2 as a heterologous host for the expression of natural product biosynthetic pathways isolated from other myxobacteria. According to the results of sequence analysis of the 16S rDNA, this moderately thermophilic isolate is closely related to Corallococcus macrosporus and was therefore named C. macrosporus GT-2. Fast growth of moderately thermophilic strains results in shorter fermentation and generation times, aspects which are of significant interest for molecular biological work as well as production of secondary metabolites. Development of a genetic manipulation system allowed the introduction of the complete myxochromide biosynthetic gene cluster, located on a transposable fragment, into the chromosome of GT-2. Genetic engineering of the biosynthetic gene cluster by promoter exchange leads to much higher production of myxochromides in the heterologous host C. macrosporus GT-2 in comparison to the original producer Stigmatella aurantiaca and to the previously described heterologous host Pseudomonas putida (600 mg/L versus 8 mg/L and 40 mg/L, respectively).
en
Novel expression hosts for complex secondary metabolite megasynthetases: Production of myxochromide in the thermopilic isolate Corallococcus macrosporus GT-2
Journal Article
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URL
https://hzi.openrepository.com/bitstream/10033/620766/1/12934_2008_Article_321.pdf
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oai:repository.helmholtz-hzi.de:10033/5785862019-08-30T11:29:46Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Medema, Marnix H
author
Kottmann, Renzo
author
Yilmaz, Pelin
author
Cummings, Matthew
author
Biggins, John B
author
Blin, Kai
author
de Bruijn, Irene
author
Chooi, Yit Heng
author
Claesen, Jan
author
Coates, R Cameron
author
Cruz-Morales, Pablo
author
Luzhetskyy, Andriy N
author
Mahmud, Taifo
author
Mast, Yvonne
author
Méndez, Carmen
author
Metsä-Ketelä, Mikko
author
Micklefield, Jason
author
Mitchell, Douglas A
author
Moore, Bradley S
author
Moreira, Leonilde M
author
Müller, Rolf
author
Duddela, Srikanth
author
Neilan, Brett A
author
Nett, Markus
author
Nielsen, Jens
author
O'Gara, Fergal
author
Oikawa, Hideaki
author
Osbourn, Anne
author
Osburne, Marcia S
author
Ostash, Bohdan
author
Payne, Shelley M
author
Pernodet, Jean-Luc
author
Düsterhus, Stephanie
author
Petricek, Miroslav
author
Piel, Jörn
author
Ploux, Olivier
author
Raaijmakers, Jos M
author
Salas, José A
author
Schmitt, Esther K
author
Scott, Barry
author
Seipke, Ryan F
author
Shen, Ben
author
Sherman, David H
author
Edwards, Daniel J
author
Sivonen, Kaarina
author
Smanski, Michael J
author
Sosio, Margherita
author
Stegmann, Evi
author
Süssmuth, Roderich D
author
Tahlan, Kapil
author
Thomas, Christopher M
author
Tang, Yi
author
Truman, Andrew W
author
Viaud, Muriel
author
Fewer, David P
author
Walton, Jonathan D
author
Walsh, Christopher T
author
Weber, Tilmann
author
van Wezel, Gilles P
author
Wilkinson, Barrie
author
Willey, Joanne M
author
Wohlleben, Wolfgang
author
Wright, Gerard D
author
Ziemert, Nadine
author
Zhang, Changsheng
author
Garg, Neha
author
Zotchev, Sergey B
author
Breitling, Rainer
author
Takano, Eriko
author
Glöckner, Frank Oliver
author
Geiger, Christoph
author
Gomez-Escribano, Juan Pablo
author
Greule, Anja
author
Hadjithomas, Michalis
author
Haines, Anthony S
author
Helfrich, Eric J N
author
Hillwig, Matthew L
author
Ishida, Keishi
author
Jones, Adam C
author
Jones, Carla S
author
Jungmann, Katrin
author
Kegler, Carsten
author
Kim, Hyun Uk
author
Kötter, Peter
author
Krug, Daniel
author
Masschelein, Joleen
author
Melnik, Alexey V
author
Mantovani, Simone M
author
Monroe, Emily A
author
Moore, Marcus
author
Moss, Nathan
author
Nützmann, Hans-Wilhelm
author
Pan, Guohui
author
Pati, Amrita
author
Petras, Daniel
author
Reen, F Jerry
author
Rosconi, Federico
author
Rui, Zhe
author
Tian, Zhenhua
author
Tobias, Nicholas J
author
Tsunematsu, Yuta
author
Wiemann, Philipp
author
Wyckoff, Elizabeth
author
Yan, Xiaohui
author
Yim, Grace
author
Yu, Fengan
author
Xie, Yunchang
author
Aigle, Bertrand
author
Apel, Alexander K
author
Balibar, Carl J
author
Balskus, Emily P
author
Barona-Gómez, Francisco
author
Bechthold, Andreas
author
Bode, Helge B
author
Borriss, Rainer
author
Brady, Sean F
author
Brakhage, Axel A
author
Caffrey, Patrick
author
Cheng, Yi-Qiang
author
Clardy, Jon
author
Cox, Russell J
author
De Mot, René
author
Donadio, Stefano
author
Donia, Mohamed S
author
van der Donk, Wilfred A
author
Dorrestein, Pieter C
author
Doyle, Sean
author
Driessen, Arnold J M
author
Ehling-Schulz, Monika
author
Entian, Karl-Dieter
author
Fischbach, Michael A
author
Gerwick, Lena
author
Gerwick, William H
author
Gross, Harald
author
Gust, Bertolt
author
Hertweck, Christian
author
Höfte, Monica
author
Jensen, Susan E
author
Ju, Jianhua
author
Katz, Leonard
author
Kaysser, Leonard
author
Klassen, Jonathan L
author
Keller, Nancy P
author
Kormanec, Jan
author
Kuipers, Oscar P
author
Kuzuyama, Tomohisa
author
Kyrpides, Nikos C
author
Kwon, Hyung-Jin
author
Lautru, Sylvie
author
Lavigne, Rob
author
Lee, Chia Y
author
Linquan, Bai
author
Liu, Xinyu
author
Liu, Wen
department
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS);Saarland University, Building A4.1, 66123 Saarbruecken, Germany.
2015-09-22T12:26:21Z
2015-08-18
Minimum Information about a Biosynthetic Gene cluster. 2015, 11 (9):625-31 Nat. Chem. Biol.
1552-4469
26284661
10.1038/nchembio.1890
http://hdl.handle.net/10033/578586
Nature chemical biology
en
Minimum Information about a Biosynthetic Gene cluster.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/578586/1/Medema%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/5818092019-08-30T11:29:17Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Lau, Stanley Ck
author
Riedel, Thomas
author
Fiebig, Anne
author
Han, James
author
Huntemann, Marcel
author
Petersen, Jörn
author
Ivanova, Natalia N
author
Markowitz, Victor
author
Woyke, Tanja
author
Göker, Markus
author
Kyrpides, Nikos C
author
Klenk, Hans-Peter
author
Qian, Pei-Yuan
2015-11-05T12:26:40Z
2015
Genome sequence of the pink-pigmented marine bacterium Loktanella hongkongensis type strain (UST950701-009P(T)), a representative of the Roseobacter group. 2015, 10:51 Stand Genomic Sci
1944-3277
26380639
10.1186/s40793-015-0050-9
http://hdl.handle.net/10033/581809
Standards in genomic sciences
Loktanella hongkongensis UST950701-009P(T) is a Gram-negative, non-motile and rod-shaped bacterium isolated from a marine biofilm in the subtropical seawater of Hong Kong. When growing as a monospecies biofilm on polystyrene surfaces, this bacterium is able to induce larval settlement and metamorphosis of a ubiquitous polychaete tubeworm Hydroides elegans. The inductive cues are low-molecular weight compounds bound to the exopolymeric matrix of the bacterial cells. In the present study we describe the features of L. hongkongensis strain DSM 17492(T) together with its genome sequence and annotation and novel aspects of its phenotype. The 3,198,444 bp long genome sequence encodes 3104 protein-coding genes and 57 RNA genes. The two unambiguously identified extrachromosomal replicons contain replication modules of the RepB and the Rhodobacteraceae-specific DnaA-like type, respectively.
en
Genome sequence of the pink-pigmented marine bacterium Loktanella hongkongensis type strain (UST950701-009P(T)), a representative of the Roseobacter group.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/581809/1/lau%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/5825302019-08-30T11:35:39Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Yin, Jia
author
Hoffmann, Michael
author
Bian, Xiaoying
author
Tu, Qiang
author
Yan, Fu
author
Xia, Liqiu
author
Ding, Xuezhi
author
Stewart, A Francis
author
Müller, Rolf
author
Fu, Jun
author
Zhang, Youming
department
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS);Saarland University, Building A4.1, 66123 Saarbruecken, Germany.
2015-11-23T15:32:44Z
2015
Direct cloning and heterologous expression of the salinomycin biosynthetic gene cluster from Streptomyces albus DSM41398 in Streptomyces coelicolor A3(2). 2015, 5:15081 Sci Rep
2045-2322
26459865
10.1038/srep15081
http://hdl.handle.net/10033/582530
Scientific reports
Linear plus linear homologous recombination-mediated recombineering (LLHR) is ideal for obtaining natural product biosynthetic gene clusters from pre-digested bacterial genomic DNA in one or two steps of recombineering. The natural product salinomycin has a potent and selective activity against cancer stem cells and is therefore a potential anti-cancer drug. Herein, we separately isolated three fragments of the salinomycin gene cluster (salO-orf18) from Streptomyces albus (S. albus) DSM41398 using LLHR and assembled them into intact gene cluster (106 kb) by Red/ET and expressed it in the heterologous host Streptomyces coelicolor (S. coelicolor) A3(2). We are the first to report a large genomic region from a Gram-positive strain has been cloned using LLHR. The successful reconstitution and heterologous expression of the salinomycin gene cluster offer an attractive system for studying the function of the individual genes and identifying novel and potential analogues of complex natural products in the recipient strain.
en
Direct cloning and heterologous expression of the salinomycin biosynthetic gene cluster from Streptomyces albus DSM41398 in Streptomyces coelicolor A3(2).
Article
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URL
https://hzi.openrepository.com/bitstream/10033/582530/1/Yin%20et%20al_final.pdf
File
MD5
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URL
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oai:repository.helmholtz-hzi.de:10033/5826012019-08-30T11:36:05Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Wardecki, Tina
author
Brötz, Elke
author
De Ford, Christian
author
von Loewenich, Friederike D
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Luzhetskyy, Andriy N
author
Merfort, Irmgard
department
Helmholtz Institute for Pharmaceutical Research Saarland,Saarbrücken, Saarland 66123, Germany.
2015-11-24T12:46:26Z
2015-08
Endophytic Streptomyces in the traditional medicinal plant Arnica montana L.: secondary metabolites and biological activity. 2015, 108 (2):391-402 Antonie Van Leeuwenhoek
1572-9699
26036671
10.1007/s10482-015-0492-5
http://hdl.handle.net/10033/582601
Antonie van Leeuwenhoek
Arnica montana L. is a medical plant of the Asteraceae family and grows preferably on nutrient poor soils in mountainous environments. Such surroundings are known to make plants dependent on symbiosis with other organisms. Up to now only arbuscular mycorrhizal fungi were found to act as endophytic symbiosis partners for A. montana. Here we identified five Streptomyces strains, microorganisms also known to occur as endophytes in plants and to produce a huge variety of active secondary metabolites, as inhabitants of A. montana. The secondary metabolite spectrum of these strains does not contain sesquiterpene lactones, but consists of the glutarimide antibiotics cycloheximide and actiphenol as well as the diketopiperazines cyclo-prolyl-valyl, cyclo-prolyl-isoleucyl, cyclo-prolyl-leucyl and cyclo-prolyl-phenylalanyl. Notably, genome analysis of one strain was performed and indicated a huge genome size with a high number of natural products gene clusters among which genes for cycloheximide production were detected. Only weak activity against the Gram-positive bacterium Staphylococcus aureus was revealed, but the extracts showed a marked cytotoxic activity as well as an antifungal activity against Candida parapsilosis and Fusarium verticillioides. Altogether, our results provide evidence that A. montana and its endophytic Streptomyces benefit from each other by completing their protection against competitors and pathogens and by exchanging plant growth promoting signals with nutrients.
en
Endophytic Streptomyces in the traditional medicinal plant Arnica montana L.: secondary metabolites and biological activity.
Article
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https://hzi.openrepository.com/bitstream/10033/582601/1/Wardecki%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/5834852019-08-30T11:36:05Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Lopatniuk, M
author
Ostash, B
author
Makitrynskyy, R
author
Walker, S
author
Luzhetskyy, Andriy N
author
Fedorenko, V
department
Helmholtz Institute for Pharmaceutical Research Saarland,Saarbrücken, Saarland 66123, Germany.
2015-12-09T13:27:03Z
2015-11
Testing the utility of site-specific recombinases for manipulations of genome of moenomycin producer Streptomyces ghanaensis ATCC14672. 2015, 56 (4):547-50 J. Appl. Genet.
2190-3883
25801470
10.1007/s13353-015-0283-8
http://hdl.handle.net/10033/583485
Journal of applied genetics
Streptomyces ghanaensis ATCC14672 is the producer of phosphoglycolipid antibiotics moenomycins that for almost 40 years were used worldwide as an animal feed additive. As the use of moenomycins narrows down (due to bans in the EU and some other countries), it opens the opportunity to develop much-needed antibiotics against Gram-positive human pathogens, such as cocci. It is desirable to develop ATCC14672 strains accumulating only certain members of moenomycin family which would facilitate their purification, analysis and/or chemical modification. Here we tested site-specific recombinases (SSRs) as a tool to manipulate the genome of ATCC14672 and to achieve aforementioned goals. We show that of three SSRs tested - Cre, Dre, and Flp - the first two efficiently catalyzed recombination reactions, while Flp showed no activity in ATCC14672 cells. Cre recombinase can be reused at least three times to modify ATCC14672 genome without detrimental effects, such as large-scale inversions or deletions. Properties of the generated strains and SSRs are discussed.
en
Testing the utility of site-specific recombinases for manipulations of genome of moenomycin producer Streptomyces ghanaensis ATCC14672.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/583485/1/JAG_MLO1.pdf
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oai:repository.helmholtz-hzi.de:10033/5935752019-08-30T11:36:05Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Lushchyk, Igor
author
Rückert, Christian
author
Zaburannyi, Nestor
author
Bechthold, Andreas
author
Kalinowski, Jörn
author
Luzhetskyy, Andriy N
department
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS);Saarland University, Building A4.1, 66123 Saarbruecken, Germany.
2016-01-15T15:37:09Z
2014
Complete genome sequence of producer of the glycopeptide antibiotic Aculeximycin Kutzneria albida DSM 43870T, a representative of minor genus of Pseudonocardiaceae. 2014, 15:885 BMC Genomics
1471-2164
25301375
10.1186/1471-2164-15-885
http://hdl.handle.net/10033/593575
BMC genomics
Kutzneria is a representative of a rarely observed genus of the family Pseudonocardiaceae. Kutzneria species were initially placed in the Streptosporangiaceae genus and later reconsidered to be an independent genus of the Pseudonocardiaceae. Kutzneria albida is one of the eight known members of the genus. This strain is a unique producer of the glycosylated polyole macrolide aculeximycin which is active against both bacteria and fungi. Kutzneria albida genome sequencing and analysis allow a deeper understanding of evolution of this genus of Pseudonocardiaceae, provide new insight in the phylogeny of the genus, as well as decipher the hidden secondary metabolic potential of these rare actinobacteria.
en
Complete genome sequence of producer of the glycopeptide antibiotic Aculeximycin Kutzneria albida DSM 43870T, a representative of minor genus of Pseudonocardiaceae.
Article
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https://hzi.openrepository.com/bitstream/10033/593575/1/Rebets%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/5957202019-08-30T11:36:05Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Ruiz-Cruz, Sofía
author
Espinosa, Manuel
author
Goldmann, Oliver
author
Bravo, Alicia
department
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2016-02-05T15:15:11Z
2015
Global Regulation of Gene Expression by the MafR Protein of Enterococcus faecalis. 2015, 6:1521 Front Microbiol
1664-302X
26793169
10.3389/fmicb.2015.01521
http://hdl.handle.net/10033/595720
Frontiers in microbiology
Enterococcus faecalis is a natural inhabitant of the human gastrointestinal tract. However, as an opportunistic pathogen, it is able to colonize other host niches and cause life-threatening infections. Its adaptation to new environments involves global changes in gene expression. The EF3013 gene (here named mafR) of E. faecalis strain V583 encodes a protein (MafR, 482 residues) that has sequence similarity to global response regulators of the Mga/AtxA family. The enterococcal OG1RF genome also encodes the MafR protein (gene OG1RF_12293). In this work, we have identified the promoter of the mafR gene using several in vivo approaches. Moreover, we show that MafR influences positively the transcription of many genes on a genome-wide scale. The most significant target genes encode components of PTS-type membrane transporters, components of ABC-type membrane transporters, and proteins involved in the metabolism of carbon sources. Some of these genes were previously reported to be up-regulated during the growth of E. faecalis in blood and/or in human urine. Furthermore, we show that a mafR deletion mutant strain induces a significant lower degree of inflammation in the peritoneal cavity of mice, suggesting that enterococcal cells deficient in MafR are less virulent. Our work indicates that MafR is a global transcriptional regulator. It might facilitate the adaptation of E. faecalis to particular host niches and, therefore, contribute to its potential virulence.
en
Global Regulation of Gene Expression by the MafR Protein of Enterococcus faecalis.
Article
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oai:repository.helmholtz-hzi.de:10033/6008902019-08-30T11:36:33Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Axenov-Gibanov, Denis V
author
Voytsekhovskaya, Irina V
author
Tokovenko, Bogdan T
author
Protasov, Eugeniy S
author
Gamaiunov, Stanislav V
author
Rebets, Yuriy V
author
Luzhetskyy, Andriy N
author
Timofeyev, Maxim A
department
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrucken, Germany, 3 Universität des Saarlandes–Pharmazeutische Biotechnologie, Saarbrucken, Germany.
2016-03-08T13:24:21Z
2016
Actinobacteria Isolated from an Underground Lake and Moonmilk Speleothem from the Biggest Conglomeratic Karstic Cave in Siberia as Sources of Novel Biologically Active Compounds. 2016, 11 (2):e0149216 PLoS ONE
1932-6203
26901168
10.1371/journal.pone.0149216
http://hdl.handle.net/10033/600890
PloS one
Actinobacteria isolated from unstudied ecosystems are one of the most interesting and promising sources of novel biologically active compounds. Cave ecosystems are unusual and rarely studied. Here, we report the isolation and characterization of ten new actinobacteria strains isolated from an ancient underground lake and moonmilk speleothem from the biggest conglomeratic karstic cave in Siberia with a focus on the biological activity of the obtained strains and the metabolite dereplication of one active strain. Streptomyces genera isolates from moonmilk speleothem demonstrated antibacterial and antifungal activities. Some of the strains were able to inhibit the growth of pathogenic Candida albicans.
en
Actinobacteria Isolated from an Underground Lake and Moonmilk Speleothem from the Biggest Conglomeratic Karstic Cave in Siberia as Sources of Novel Biologically Active Compounds.
Article
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URL
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URL
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oai:repository.helmholtz-hzi.de:10033/6010412019-08-30T11:35:39Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
A Elnakady, Yasser
author
Chatterjee, Indranil
author
Bischoff, Markus
author
Rohde, Manfred
author
Josten, Michaele
author
Sahl, Hans-Georg
author
Herrmann, Mathias
author
Müller, Rolf
department
Helmholtz Institute for Pharmaceutical Research Saarland,
Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland
University, Saarbrücken, Germany.
2016-03-09T15:48:40Z
2016
Investigations to the Antibacterial Mechanism of Action of Kendomycin. 2016, 11 (1):e0146165 PLoS ONE
1932-6203
26795276
10.1371/journal.pone.0146165
http://hdl.handle.net/10033/601041
PloS one
The emergence of bacteria that are resistant to many currently used drugs emphasizes the need to discover and develop new antibiotics that are effective against such multi-resistant strains. Kendomycin is a novel polyketide that has a unique quinone methide ansa structure and various biological properties. This compound exhibits strong antibacterial activity against Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Despite the promise of kendomycinin in several therapeutic areas, its mode of action has yet to be identified.
en
Investigations to the Antibacterial Mechanism of Action of Kendomycin.
Article
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URL
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URL
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oai:repository.helmholtz-hzi.de:10033/6013662019-08-30T11:36:05Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Tu, Qiang
author
Herrmann, Jennifer
author
Hu, Shengbiao
author
Raju, Ritesh
author
Bian, Xiaoying
author
Zhang, Youming
author
Müller, Rolf
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland 9 University, 66123 Saarbrücken, Germany.
2016-03-15T15:07:40Z
2016
Genetic engineering and heterologous expression of the disorazol biosynthetic gene cluster via Red/ET recombineering. 2016, 6:21066 Sci Rep
2045-2322
26875499
10.1038/srep21066
http://hdl.handle.net/10033/601366
Scientific reports
Disorazol, a macrocyclic polykitide produced by the myxobacterium Sorangium cellulosum So ce12 and it is reported to have potential cytotoxic activity towards several cancer cell lines, including multi-drug resistant cells. The disorazol biosynthetic gene cluster (dis) from Sorangium cellulosum (So ce12) was identified by transposon mutagenesis and cloned in a bacterial artificial chromosome (BAC) library. The 58-kb dis core gene cluster was reconstituted from BACs via Red/ET recombineering and expressed in Myxococcus xanthus DK1622. For the first time ever, a myxobacterial trans-AT polyketide synthase has been expressed heterologously in this study. Expression in M. xanthus allowed us to optimize the yield of several biosynthetic products using promoter engineering. The insertion of an artificial synthetic promoter upstream of the disD gene encoding a discrete acyl transferase (AT), together with an oxidoreductase (Or), resulted in 7-fold increase in disorazol production. The successful reconstitution and expression of the genetic sequences encoding for these promising cytotoxic compounds will allow combinatorial biosynthesis to generate novel disorazol derivatives for further bioactivity evaluation.
en
Genetic engineering and heterologous expression of the disorazol biosynthetic gene cluster via Red/ET recombineering.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6020942019-08-30T11:36:04Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Preisitsch, Michael
author
Heiden, Stefan E
author
Beerbaum, Monika
author
Niedermeyer, Timo H J
author
Schneefeld, Marie
author
Herrmann, Jennifer
author
Kumpfmüller, Jana
author
Thürmer, Andrea
author
Neidhardt, Inga
author
Wiesner, Christoph
author
Daniel, Rolf
author
Müller, Rolf
author
Bange, Franz-Christoph
author
Schmieder, Peter
author
Schweder, Thomas
author
Mundt, Sabine
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland 9 University, 66123 Saarbrücken, Germany.
2016-03-17T15:33:33Z
2016
Effects of Halide Ions on the Carbamidocyclophane Biosynthesis in Nostoc sp. CAVN2. 2016, 14 (1): Mar Drugs
1660-3397
26805858
10.3390/md14010021
http://hdl.handle.net/10033/602094
Marine drugs
In this study, the influence of halide ions on [7.7]paracyclophane biosynthesis in the cyanobacterium Nostoc sp. CAVN2 was investigated. In contrast to KI and KF, supplementation of the culture medium with KCl or KBr resulted not only in an increase of growth but also in an up-regulation of carbamidocyclophane production. LC-MS analysis indicated the presence of chlorinated, brominated, but also non-halogenated derivatives. In addition to 22 known cylindrocyclophanes and carbamidocyclophanes, 27 putative congeners have been detected. Nine compounds, carbamidocyclophanes M-U, were isolated, and their structural elucidation by 1D and 2D NMR experiments in combination with HRMS and ECD analysis revealed that they are brominated analogues of chlorinated carbamidocyclophanes. Quantification of the carbamidocyclophanes showed that chloride is the preferably utilized halide, but incorporation is reduced in the presence of bromide. Evaluation of the antibacterial activity of 30 [7.7]paracyclophanes and related derivatives against selected pathogenic Gram-positive and Gram-negative bacteria exhibited remarkable effects especially against methicillin- and vancomycin-resistant staphylococci and Mycobacterium tuberculosis. For deeper insights into the mechanisms of biosynthesis, the carbamidocyclophane biosynthetic gene cluster in Nostoc sp. CAVN2 was studied. The gene putatively coding for the carbamoyltransferase has been identified. Based on bioinformatic analyses, a possible biosynthetic assembly is discussed.
en
Effects of Halide Ions on the Carbamidocyclophane Biosynthesis in Nostoc sp. CAVN2.
Article
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URL
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File
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oai:repository.helmholtz-hzi.de:10033/6052862019-08-30T11:33:30Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Zaburannyi, Nestor
author
Bunk, Boyke
author
Maier, Josef
author
Overmann, Jörg
author
Müller, Rolf
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.
2016-04-14T14:45:33Z
2016
Genome Analysis of the Fruiting Body-Forming Myxobacterium Chondromyces crocatus Reveals High Potential for Natural Product Biosynthesis. 2016, 82 (6):1945-57 Appl. Environ. Microbiol.
1098-5336
26773087
10.1128/AEM.03011-15
http://hdl.handle.net/10033/605286
Applied and environmental microbiology
Here, we report the complete genome sequence of the type strain of the myxobacterial genus Chondromyces, Chondromyces crocatus Cm c5. It presents one of the largest prokaryotic genomes featuring a single circular chromosome and no plasmids. Analysis revealed an enlarged set of tRNA genes, along with reduced pressure on preferred codon usage compared to that of other bacterial genomes. The large coding capacity and the plethora of encoded secondary metabolite biosynthetic gene clusters are in line with the capability of Cm c5 to produce an arsenal of antibacterial, antifungal, and cytotoxic compounds. Known pathways of the ajudazol, chondramide, chondrochloren, crocacin, crocapeptin, and thuggacin compound families are complemented by many more natural compound biosynthetic gene clusters in the chromosome. Whole-genome comparison of the fruiting-body-forming type strain (Cm c5, DSM 14714) to an accustomed laboratory strain which has lost this ability (nonfruiting phenotype, Cm c5 fr-) revealed genetic changes in three loci. In addition to the low synteny found with the closest sequenced representative of the same family, Sorangium cellulosum, extensive genetic information duplication and broad application of eukaryotic-type signal transduction systems are hallmarks of this 11.3-Mbp prokaryotic genome.
en
Genome Analysis of the Fruiting Body-Forming Myxobacterium Chondromyces crocatus Reveals High Potential for Natural Product Biosynthesis.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6058602019-08-30T11:32:16Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Knapp, Andreas
author
Voget, Sonja
author
Gao, Rong
author
Zaburannyi, Nestor
author
Krysciak, Dagmar
author
Breuer, Michael
author
Hauer, Bernhard
author
Streit, Wolfgang R
author
Müller, Rolf
author
Daniel, Rolf
author
Jaeger, Karl-Erich
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland 9 University, 66123 Saarbrücken, Germany.
2016-04-19T09:34:05Z
2015-10-17
Mutations improving production and secretion of extracellular lipase by Burkholderia glumae PG1. 2015: Appl. Microbiol. Biotechnol.
1432-0614
26476653
10.1007/s00253-015-7041-z
http://hdl.handle.net/10033/605860
Applied microbiology and biotechnology
Burkholderia glumae is a Gram-negative phytopathogenic bacterium known as the causative agent of rice panicle blight. Strain B. glumae PG1 is used for the production of a biotechnologically relevant lipase, which is secreted into the culture supernatant via a type II secretion pathway. We have comparatively analyzed the genome sequences of B. glumae PG1 wild type and a lipase overproducing strain obtained by classical strain mutagenesis. Among a total number of 72 single nucleotide polymorphisms (SNPs) identified in the genome of the production strain, two were localized in front of the lipAB operon and were analyzed in detail. Both mutations contribute to a 100-fold overproduction of extracellular lipase in B. glumae PG1 by affecting transcription of the lipAB operon and efficiency of lipase secretion. We analyzed each of the two SNPs separately and observed a stronger influence of the promoter mutation than of the signal peptide modification but also a cumulative effect of both mutations. Furthermore, fusion of the mutated LipA signal peptide resulted in a 2-fold increase in secretion of the heterologous reporter alkaline phosphatase from Escherichia coli.
Mutations improving production and secretion of extracellular lipase by Burkholderia glumae PG1.
Article
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oai:repository.helmholtz-hzi.de:10033/6106742019-08-30T11:28:24Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Völlger, Lena
author
Akong-Moore, Kathryn
author
Cox, Linda
author
Goldmann, Oliver
author
Wang, Yanming
author
Schäfer, Simon T
author
Naim, Hassan Y
author
Nizet, Victor
author
von Köckritz-Blickwede, Maren
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-05-25T08:54:40Z
2016-07
Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils. 2016, 36 (3): Biosci. Rep.
1573-4935
27129288
10.1042/BSR20160031
http://hdl.handle.net/10033/610674
Bioscience reports
Neutrophil extracellular trap (NET) formation is a significant innate immune defense mechanism against microbial infection that complements other neutrophil functions including phagocytosis and degranulation of antimicrobial peptides. NETs are decondensed chromatin structures in which antimicrobial components (histones, antimicrobial peptides and proteases) are deployed and mediate immobilization of microbes. Here we describe an effect of iron chelation on the phenotype of NET formation. Iron-chelating agent desferrioxamine (DFO) showed a modest but significant induction of NETs by freshly isolated human neutrophils as visualized and quantified by immunocytochemistry against histone-DNA complexes. Further analyses revealed that NET induction by iron chelation required NADPH-dependent production of reactive oxygen species (ROS) as well as protease and peptidyl-arginine-deiminase 4 (PAD4) activities, three key mechanistic pathways previously linked to NET formation. Our results demonstrate that iron chelation by DFO contributes to the formation of NETs and suggest a target for pharmacological manipulation of NET activity.
en
Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/610674/1/V%c3%b6llger%20et%20al.pdf
File
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URL
https://hzi.openrepository.com/bitstream/10033/610674/6/V%c3%b6llger%20et%20al.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/6112562019-08-30T11:31:49Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Lohße, Anna
author
Kolinko, Isabel
author
Raschdorf, Oliver
author
Uebe, René
author
Borg, Sarah
author
Brachmann, Andreas
author
Plitzko, Jürgen M
author
Müller, Rolf
author
Zhang, Youming
author
Schüler, Dirk
department
Helmholtz-Institut für pharmaceutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2016-05-31T14:11:54Z
2016-05-15
Overproduction of Magnetosomes by Genomic Amplification of Biosynthesis-Related Gene Clusters in a Magnetotactic Bacterium. 2016, 82 (10):3032-41 Appl. Environ. Microbiol.
1098-5336
26969709
10.1128/AEM.03860-15
http://hdl.handle.net/10033/611256
Applied and environmental microbiology
Magnetotactic bacteria biosynthesize specific organelles, the magnetosomes, which are membrane-enclosed crystals of a magnetic iron mineral that are aligned in a linear chain. The number and size of magnetosome particles have to be critically controlled to build a sensor sufficiently strong to ensure the efficient alignment of cells within Earth's weak magnetic field while at the same time minimizing the metabolic costs imposed by excessive magnetosome biosynthesis. Apart from their biological function, bacterial magnetosomes have gained considerable interest since they provide a highly useful model for prokaryotic organelle formation and represent biogenic magnetic nanoparticles with exceptional properties. However, potential applications have been hampered by the difficult cultivation of these fastidious bacteria and their poor yields of magnetosomes. In this study, we found that the size and number of magnetosomes within the cell are controlled by many different Mam and Mms proteins. We present a strategy for the overexpression of magnetosome biosynthesis genes in the alphaproteobacterium Magnetospirillum gryphiswaldense by chromosomal multiplication of individual and multiple magnetosome gene clusters via transposition. While stepwise amplification of the mms6 operon resulted in the formation of increasingly larger crystals (increase of ∼35%), the duplication of all major magnetosome operons (mamGFDC, mamAB, mms6, and mamXY, comprising 29 genes in total) yielded an overproducing strain in which magnetosome numbers were 2.2-fold increased. We demonstrate that the tuned expression of the mam and mms clusters provides a powerful strategy for the control of magnetosome size and number, thereby setting the stage for high-yield production of tailored magnetic nanoparticles by synthetic biology approaches.
en
Overproduction of Magnetosomes by Genomic Amplification of Biosynthesis-Related Gene Clusters in a Magnetotactic Bacterium.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/611256/1/Loh%c3%9fe%20et%20al.pdf
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Lohße et al.pdf
URL
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oai:repository.helmholtz-hzi.de:10033/6115312019-08-30T11:26:13Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Fengler, Vera H I
author
Macheiner, Tanja
author
Kessler, Sonja M
author
Czepukojc, Beate
author
Gemperlein, Katja
author
Müller, Rolf
author
Kiemer, Alexandra K
author
Magnes, Christoph
author
Haybaeck, Johannes
author
Lackner, Carolin
author
Sargsyan, Karine
department
Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken.
2016-06-02T13:19:21Z
2016
Susceptibility of Different Mouse Wild Type Strains to Develop Diet-Induced NAFLD/AFLD-Associated Liver Disease. 2016, 11 (5):e0155163 PLoS ONE
1932-6203
27167736
10.1371/journal.pone.0155163
http://hdl.handle.net/10033/611531
PloS one
Although non-alcoholic and alcoholic fatty liver disease have been intensively studied, concerning pathophysiological mechanisms are still incompletely understood. This may be due to the use of different animal models and resulting model-associated variation. Therefore, this study aimed to compare three frequently used wild type mouse strains in their susceptibility to develop diet-induced features of non-alcoholic/alcoholic fatty liver disease. Fatty liver disease associated clinical, biochemical, and histological features in C57BL/6, CD-1, and 129Sv WT mice were induced by (i) high-fat diet feeding, (ii) ethanol feeding only, and (iii) the combination of high-fat diet and ethanol feeding. Hepatic and subcutaneous adipose lipid profiles were compared in CD-1 and 129Sv mice. Additionally hepatic fatty acid composition was determined in 129Sv mice. In C57BL/6 mice dietary regimens resulted in heterogeneous hepatic responses, ranging from pronounced steatosis and inflammation to a lack of any features of fatty liver disease. Liver-related serum biochemistry showed high deviations within the regimen groups. CD-1 mice did not exhibit significant changes in metabolic and liver markers and developed no significant steatosis or inflammation as a response to dietary regimens. Although 129Sv mice showed no weight gain, this strain achieved most consistent features of fatty liver disease, apparent from concentration alterations of liver-related serum biochemistry as well as moderate steatosis and inflammation as a result of all dietary regimens. Furthermore, the hepatic lipid profile as well as the fatty acid composition of 129Sv mice were considerably altered, upon feeding the different dietary regimens. Accordingly, diet-induced non-alcoholic/alcoholic fatty liver disease is most consistently promoted in 129Sv mice compared to C57BL/6 and CD-1 mice. As a conclusion, this study demonstrates the importance of genetic background of used mouse strains for modeling diet-induced non-alcoholic/alcoholic fatty liver disease.
en
Susceptibility of Different Mouse Wild Type Strains to Develop Diet-Induced NAFLD/AFLD-Associated Liver Disease.
Article
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oai:repository.helmholtz-hzi.de:10033/6137112019-08-30T11:33:24Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Braig, Simone
author
Sebastian Schmidt, B U
author
Stoiber, Katharina
author
Händel, Chris
author
Möhn, Till
author
Werz, Oliver
author
Müller, Rolf
author
Zahler, Stefan
author
Koeberle, Andreas
author
Käs, Josef A
author
Vollmar, Angelika M
department
Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken.
2016-06-20T13:22:28Z
2015-08-05
Pharmacological targeting of membrane rigidity: implications on cancer cell migration and invasion 2015, 17 (8):083007 New Journal of Physics
1367-2630
10.1088/1367-2630/17/8/083007
http://hdl.handle.net/10033/613711
New Journal of Physics
Pharmacological targeting of membrane rigidity: implications on cancer cell migration and invasion
Article
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oai:repository.helmholtz-hzi.de:10033/6143862019-08-30T11:27:16Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Horst, Sarah A
author
Itzek, Andreas
author
Klos, Andreas
author
Beineke, Andreas
author
Medina, Eva
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-06-23T08:45:45Z
2015
Differential Contributions of the Complement Anaphylotoxin Receptors C5aR1 and C5aR2 to the Early Innate Immune Response against Staphylococcus aureus Infection. 2015, 4 (4):722-38 Pathogens
2076-0817
26512700
10.3390/pathogens4040722
http://hdl.handle.net/10033/614386
Pathogens (Basel, Switzerland)
The complement anaphylatoxin C5a contributes to host defense against Staphylococcus aureus. In this study, we investigated the functional role of the two known C5a receptors, C5aR1 and C5aR2, in the host response to S. aureus. We found that C5aR1(-/)(-) mice exhibited greater susceptibility to S. aureus bloodstream infection than wild type and C5aR2(-/)(-) mice, as demonstrated by the significantly higher bacterial loads in the kidneys and heart at 24 h of infection, and by the higher levels of inflammatory IL-6 in serum. Histological and immunohistochemistry investigation of infected kidneys at 24 h after bacterial inoculation revealed a discrete infiltration of neutrophils in wild type mice but already well-developed abscesses consisting of bacterial clusters surrounded by a large number of neutrophils in both C5aR1(-/)(-) and C5aR2(-/)(-) mice. Furthermore, blood neutrophils from C5aR1(-/)(-) mice were less efficient than those from wild type or C5aR2(-/)(-) mice at killing S. aureus. The requirement of C5aR1 for efficient killing of S. aureus was also demonstrated in human blood after disrupting C5a-C5aR1 signaling using specific inhibitors. These results demonstrated a role for C5aR1 in S. aureus clearance as well as a role for both C5aR1 and C5aR2 in the orchestration of the inflammatory response during infection.
en
Differential Contributions of the Complement Anaphylotoxin Receptors C5aR1 and C5aR2 to the Early Innate Immune Response against Staphylococcus aureus Infection.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/614386/1/Horst%20et%20al.pdf
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Horst et al.pdf.txt
oai:repository.helmholtz-hzi.de:10033/6148892019-08-30T11:26:13Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Wenzel, Silke C
author
Hoffmann, Holger
author
Zhang, Jidong
author
Debussche, Laurent
author
Haag-Richter, Sabine
author
Kurz, Michael
author
Nardi, Frederico
author
Lukat, Peer
author
Kochems, Irene
author
Tietgen, Heiko
author
Schummer, Dietmar
author
Nicolas, Jean-Paul
author
Calvet, Loreley
author
Czepczor, Valerie
author
Vrignaud, Patricia
author
Mühlenweg, Agnes
author
Pelzer, Stefan
author
Müller, Rolf
author
Brönstrup, Mark
department
Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken.
2016-06-28T11:54:30Z
2015-12-14
Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships. 2015, 54 (51):15560-4 Angew. Chem. Int. Ed. Engl.
1521-3773
26514647
10.1002/anie.201508277
http://hdl.handle.net/10033/614889
Angewandte Chemie (International ed. in English)
The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model.
en
Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships.
Article
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oai:repository.helmholtz-hzi.de:10033/6149182019-08-30T11:26:13Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Kessler, Sonja M
author
Laggai, Stephan
author
Van Wonterg, Elien
author
Gemperlein, Katja
author
Müller, Rolf
author
Haybaeck, Johannes
author
Vandenbroucke, Roosmarijn E
author
Ogris, Manfred
author
Libert, Claude
author
Kiemer, Alexandra K
department
Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken.
2016-06-28T14:14:32Z
2016
Transient Hepatic Overexpression of Insulin-Like Growth Factor 2 Induces Free Cholesterol and Lipid Droplet Formation. 2016, 7:147 Front Physiol
1664-042X
27199763
10.3389/fphys.2016.00147
http://hdl.handle.net/10033/614918
Frontiers in physiology
Although insulin-like growth factor 2 (IGF2) has been reported to be overexpressed in steatosis and steatohepatitis, a causal role of IGF2 in steatosis development remains elusive. Aim of our study was to decipher the role of IGF2 in steatosis development. Hydrodynamic gene delivery of an Igf2 plasmid used for transient Igf2 overexpression employing codon-optimized plasmid DNA resulted in a strong induction of hepatic Igf2 expression. The exogenously delivered Igf2 had no influence on endogenous Igf2 expression. The downstream kinase AKT was activated in Igf2 animals. Decreased ALT levels mirrored the cytoprotective effect of IGF2. Serum cholesterol was increased and sulfo-phospho-vanillin colorimetric assay confirmed lipid accumulation in Igf2-livers while no signs of inflammation were observed. Interestingly, hepatic cholesterol and phospholipids, determined by thin layer chromatography, and free cholesterol by filipin staining, were specifically increased. Lipid droplet (LD) size was not changed, but their number was significantly elevated. Furthermore, free cholesterol, which can be stored in LDs and has been reported to be critical for steatosis progression, was elevated in Igf2 overexpressing mice. Accordingly, Hmgcr/HmgCoAR was upregulated. To have a closer look at de novo lipid synthesis we investigated expression of the lipogenic transcription factor SREBF1 and its target genes. SREBF1 was induced and also SREBF1 target genes were slightly upregulated. Interestingly, the expression of Cpt1a, which is responsible for mitochondrial fatty acid oxidation, was induced. Hepatic IGF2 expression induces a fatty liver, characterized by increased cholesterol and phospholipids leading to accumulation of LDs. We therefore suggest a causal role for IGF2 in hepatic lipid accumulation.
en
Transient Hepatic Overexpression of Insulin-Like Growth Factor 2 Induces Free Cholesterol and Lipid Droplet Formation.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/614918/1/Kessler%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6159792019-08-30T11:26:42Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Zhang, Siwei
author
Schneider, Lina S
author
Vick, Binje
author
Grunert, Michaela
author
Jeremias, Irmela
author
Menche, Dirk
author
Müller, Rolf
author
Vollmar, Angelika M
author
Liebl, Johanna
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland 9 University, 66123 Saarbrücken, Germany.
2016-07-12T10:56:50Z
2015-12-22
Anti-leukemic effects of the V-ATPase inhibitor Archazolid A. 2015, 6 (41):43508-28 Oncotarget
1949-2553
26496038
10.18632/oncotarget.6180
http://hdl.handle.net/10033/615979
Oncotarget
Prognosis for patients suffering from T-ALL is still very poor and new strategies for T-ALL treatment are urgently needed. Our study shows potent anti-leukemic effects of the myxobacterial V-ATPase inhibitor Archazolid A. Archazolid A reduced growth and potently induced death of leukemic cell lines and human leukemic samples. By inhibiting lysosomal acidification, Archazolid A blocked activation of the Notch pathway, however, this was not the mechanism of V-ATPase inhibition relevant for cell death induction. In fact, V-ATPase inhibition by Archazolid A decreased the anti-apoptotic protein survivin. As underlying mode of action, this work is in line with recent studies from our group demonstrating that Archazolid A induced S-phase cell cycle arrest by interfering with the iron metabolism in leukemic cells. Our study provides evidence for V-ATPase inhibition as a potential new therapeutic option for T-ALL.
en
Anti-leukemic effects of the V-ATPase inhibitor Archazolid A.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/615979/1/Zhang%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6169542019-08-30T11:25:43Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Tu, Qiang
author
Yin, Jia
author
Fu, Jun
author
Herrmann, Jennifer
author
Li, Yuezhong
author
Yin, Yulong
author
Stewart, A Francis
author
Müller, Rolf
author
Zhang, Youming
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland 9 University, 66123 Saarbrücken, Germany.
2016-07-14T08:29:43Z
2016
Room temperature electrocompetent bacterial cells improve DNA transformation and recombineering efficiency. 2016, 6:24648 Sci Rep
2045-2322
27095488
10.1038/srep24648
http://hdl.handle.net/10033/616954
Scientific reports
Bacterial competent cells are essential for cloning, construction of DNA libraries, and mutagenesis in every molecular biology laboratory. Among various transformation methods, electroporation is found to own the best transformation efficiency. Previous electroporation methods are based on washing and electroporating the bacterial cells in ice-cold condition that make them fragile and prone to death. Here we present simple temperature shift based methods that improve DNA transformation and recombineering efficiency in E. coli and several other gram-negative bacteria thereby economizing time and cost. Increased transformation efficiency of large DNA molecules is a significant advantage that might facilitate the cloning of large fragments from genomic DNA preparations and metagenomics samples.
en
Room temperature electrocompetent bacterial cells improve DNA transformation and recombineering efficiency.
Article
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oai:repository.helmholtz-hzi.de:10033/6184992019-08-30T11:33:05Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Horbal, L
author
Luzhetskyy, Andriy N
department
Helmholtz Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2016-08-17T14:06:58Z
2016-09
Dual control system - A novel scaffolding architecture of an inducible regulatory device for the precise regulation of gene expression. 2016, 37:11-23 Metab. Eng.
1096-7184
27040671
10.1016/j.ymben.2016.03.008
http://hdl.handle.net/10033/618499
Metabolic engineering
Here, we present a novel scaffolding architecture of an inducible regulatory device. This dual control system is completely silent in the off stage and is coupled to the regulation of gene expression at both the transcriptional and translational levels. This system also functions as an AND gate. We demonstrated the effectiveness of the cumate-riboswitch dual control system for the control of pamamycin production in Streptomyces albus. Placing the cre recombinase gene under the control of this system permitted the construction of synthetic devices with non-volatile memory that sense the signal and respond by altering DNA at the chromosomal level, thereby producing changes that are heritable. In addition, we present a library of synthetic inducible promoters based on the previously described cumate switch. With only one inducer and different promoters, we demonstrate that simultaneous modulation of the expression of several genes to different levels in various operons is possible. Because all modules of the AND gates are functional in bacteria other than Streptomyces, we anticipate that these regulatory devices can be used to control gene expression in other Actinobacteria. The features described in this study make these systems promising tools for metabolic engineering and biotechnology in Actinobacteria.
en
openAccess
Dual control system - A novel scaffolding architecture of an inducible regulatory device for the precise regulation of gene expression.
Article
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oai:repository.helmholtz-hzi.de:10033/6184972019-08-30T11:31:49Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Bilyk, Oksana
author
Sekurova, Olga N
author
Zotchev, Sergey B
author
Luzhetskyy, Andriy N
department
Helmholtz Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2016-08-17T13:17:27Z
2016
Cloning and Heterologous Expression of the Grecocycline Biosynthetic Gene Cluster. 2016, 11 (7):e0158682 PLoS ONE
1932-6203
27410036
10.1371/journal.pone.0158682
http://hdl.handle.net/10033/618497
PloS one
Transformation-associated recombination (TAR) in yeast is a rapid and inexpensive method for cloning and assembly of large DNA fragments, which relies on natural homologous recombination. Two vectors, based on p15a and F-factor replicons that can be maintained in yeast, E. coli and streptomycetes have been constructed. These vectors have been successfully employed for assembly of the grecocycline biosynthetic gene cluster from Streptomyces sp. Acta 1362. Fragments of the cluster were obtained by PCR and transformed together with the "capture" vector into the yeast cells, yielding a construct carrying the entire gene cluster. The obtained construct was heterologously expressed in S. albus J1074, yielding several grecocycline congeners. Grecocyclines have unique structural moieties such as a dissacharide side chain, an additional amino sugar at the C-5 position and a thiol group. Enzymes from this pathway may be used for the derivatization of known active angucyclines in order to improve their desired biological properties.
en
openAccess
Cloning and Heterologous Expression of the Grecocycline Biosynthetic Gene Cluster.
Article
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oai:repository.helmholtz-hzi.de:10033/6205642019-08-30T11:25:43Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Wang, Mingxun
author
Carver, Jeremy J
author
Phelan, Vanessa V
author
Sanchez, Laura M
author
Garg, Neha
author
Peng, Yao
author
Nguyen, Don Duy
author
Watrous, Jeramie
author
Kapono, Clifford A
author
Luzzatto-Knaan, Tal
author
Porto, Carla
author
Bouslimani, Amina
author
Melnik, Alexey V
author
Meehan, Michael J
author
Liu, Wei-Ting
author
Crüsemann, Max
author
Boudreau, Paul D
author
Esquenazi, Eduardo
author
Sandoval-Calderón, Mario
author
Kersten, Roland D
author
Pace, Laura A
author
Quinn, Robert A
author
Duncan, Katherine R
author
Hsu, Cheng-Chih
author
Floros, Dimitrios J
author
Gavilan, Ronnie G
author
Kleigrewe, Karin
author
Northen, Trent
author
Dutton, Rachel J
author
Parrot, Delphine
author
Carlson, Erin E
author
Aigle, Bertrand
author
Michelsen, Charlotte F
author
Jelsbak, Lars
author
Sohlenkamp, Christian
author
Pevzner, Pavel
author
Edlund, Anna
author
McLean, Jeffrey
author
Piel, Jörn
author
Murphy, Brian T
author
Gerwick, Lena
author
Liaw, Chih-Chuang
author
Yang, Yu-Liang
author
Humpf, Hans-Ulrich
author
Maansson, Maria
author
Keyzers, Robert A
author
Sims, Amy C
author
Johnson, Andrew R
author
Sidebottom, Ashley M
author
Sedio, Brian E
author
Klitgaard, Andreas
author
Larson, Charles B
author
Boya P, Cristopher A
author
Torres-Mendoza, Daniel
author
Gonzalez, David J
author
Silva, Denise B
author
Marques, Lucas M
author
Demarque, Daniel P
author
Pociute, Egle
author
O'Neill, Ellis C
author
Briand, Enora
author
Helfrich, Eric J N
author
Granatosky, Eve A
author
Glukhov, Evgenia
author
Ryffel, Florian
author
Houson, Hailey
author
Mohimani, Hosein
author
Kharbush, Jenan J
author
Zeng, Yi
author
Vorholt, Julia A
author
Kurita, Kenji L
author
Charusanti, Pep
author
McPhail, Kerry L
author
Nielsen, Kristian Fog
author
Vuong, Lisa
author
Elfeki, Maryam
author
Traxler, Matthew F
author
Engene, Niclas
author
Koyama, Nobuhiro
author
Vining, Oliver B
author
Baric, Ralph
author
Silva, Ricardo R
author
Mascuch, Samantha J
author
Tomasi, Sophie
author
Jenkins, Stefan
author
Macherla, Venkat
author
Hoffman, Thomas
author
Agarwal, Vinayak
author
Williams, Philip G
author
Dai, Jingqui
author
Neupane, Ram
author
Gurr, Joshua
author
Rodríguez, Andrés M C
author
Lamsa, Anne
author
Zhang, Chen
author
Dorrestein, Kathleen
author
Duggan, Brendan M
author
Almaliti, Jehad
author
Allard, Pierre-Marie
author
Phapale, Prasad
author
Nothias, Louis-Felix
author
Alexandrov, Theodore
author
Litaudon, Marc
author
Wolfender, Jean-Luc
author
Kyle, Jennifer E
author
Metz, Thomas O
author
Peryea, Tyler
author
Nguyen, Dac-Trung
author
VanLeer, Danielle
author
Shinn, Paul
author
Jadhav, Ajit
author
Müller, Rolf
author
Waters, Katrina M
author
Shi, Wenyuan
author
Liu, Xueting
author
Zhang, Lixin
author
Knight, Rob
author
Jensen, Paul R
author
Palsson, Bernhard Ø
author
Pogliano, Kit
author
Linington, Roger G
author
Gutiérrez, Marcelino
author
Lopes, Norberto P
author
Gerwick, William H
author
Moore, Bradley S
author
Dorrestein, Pieter C
author
Bandeira, Nuno
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2016-10-27T09:10:59Z
2016-08-09
Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. 2016, 34 (8):828-37 Nat. Biotechnol.
1546-1696
27504778
10.1038/nbt.3597
http://hdl.handle.net/10033/620564
Nature biotechnology
The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of 'living data' through continuous reanalysis of deposited data.
Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking.
Article
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oai:repository.helmholtz-hzi.de:10033/6206172019-08-30T11:34:18Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Chen, Jinsong
author
Liu, Mei
author
Liu, Xueting
author
Miao, Jin
author
Fu, Chengzhang
author
Gao, Heyong
author
Müller, Rolf
author
Zhang, Qing
author
Zhang, Lixin
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2016-12-02T09:14:07Z
2016-03
Interrogation of Streptomyces avermitilis for efficient production of avermectins 2016, 1 (1):7 Synthetic and Systems Biotechnology
2405805X
10.1016/j.synbio.2016.03.002
http://hdl.handle.net/10033/620617
Synthetic and Systems Biotechnology
Interrogation of Streptomyces avermitilis for efficient production of avermectins
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620617/1/Chen%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6206742019-08-30T11:27:46Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Horbal, Liliya
author
Ostash, Bohdan
author
Luzhetskyy, Andriy N
author
Walker, Suzanne
author
Kalinowski, Jorn
author
Fedorenko, Victor
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2016-12-19T12:49:33Z
2016-09
A gene cluster for the biosynthesis of moenomycin family antibiotics in the genome of teicoplanin producer Actinoplanes teichomyceticus. 2016, 100 (17):7629-38 Appl. Microbiol. Biotechnol.
1432-0614
27344593
10.1007/s00253-016-7685-3
http://hdl.handle.net/10033/620674
Applied microbiology and biotechnology
Moenomycins are phosphoglycolipid antibiotics notable for their extreme potency, unique mode of action, and proven record of use in animal nutrition without selection for resistant microflora. There is a keen interest in manipulation of structures of moenomycins in order to better understand their structure-activity relationships and to generate improved analogs. Only two almost identical moenomycin biosynthetic gene clusters are known, limiting our knowledge of the evolution of moenomycin pathways and our ability to genetically diversify them. Here, we report a novel gene cluster (tchm) that directs production of the phosphoglycolipid teichomycin in Actinoplanes teichomyceticus. Its overall genetic architecture is significantly different from that of the moenomycin biosynthesis (moe) gene clusters of Streptomyces ghanaensis and Streptomyces clavuligerus, featuring multiple gene rearrangements and two novel structural genes. Involvement of the tchm cluster in teichomycin biosynthesis was confirmed via heterologous co-expression of amidotransferase tchmH5 and moe genes. Our work sets the background for further engineering of moenomycins and for deeper inquiries into the evolution of this fascinating biosynthetic pathway.
en
A gene cluster for the biosynthesis of moenomycin family antibiotics in the genome of teicoplanin producer Actinoplanes teichomyceticus.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620674/1/Horbal%20et%20al.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/620674/2/Supplement%20S1_1.pdf
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URL
https://hzi.openrepository.com/bitstream/10033/620674/7/Horbal%20et%20al.pdf.txt
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URL
https://hzi.openrepository.com/bitstream/10033/620674/9/Supplement%20S1_1.pdf.txt
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Supplement S1_1.pdf.txt
oai:repository.helmholtz-hzi.de:10033/6206882019-08-30T11:33:57Zcom_10033_311308com_10033_620618col_10033_620619col_10033_559591col_10033_620561
Helmholtz Zentrum für Infektionsforschung Repository
author
Bock, Tobias
author
Volz, Carsten
author
Hering, Vanessa
author
Scrima, Andrea
author
Müller, Rolf
author
Blankenfeldt, Wulf
department
Hel,holtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-01-09T15:31:16Z
2016-12-09
The AibR-isovaleryl coenzyme A regulator and its DNA binding site - a model for the regulation of alternative de novo isovaleryl coenzyme A biosynthesis in Myxococcus xanthus. 2016 Nucleic Acids Res.
1362-4962
27940564
10.1093/nar/gkw1238
http://hdl.handle.net/10033/620688
Nucleic acids research
Isovaleryl coenzyme A (IV-CoA) is an important building block of iso-fatty acids. In myxobacteria, IV-CoA is essential for the formation of signaling molecules involved in fruiting body formation. Leucine degradation is the common source of IV-CoA, but a second, de novo biosynthetic route to IV-CoA termed AIB (alternative IV-CoA biosynthesis) was recently discovered in M. xanthus The AIB-operon contains the TetR-like transcriptional regulator AibR, which we characterize in this study. We demonstrate that IV-CoA binds AibR with micromolar affinity and show by gelshift experiments that AibR interacts with the promoter region of the AIB-operon once IV-CoA is present. We identify an 18-bp near-perfect palindromic repeat as containing the AibR operator and provide evidence that AibR also controls an additional genomic locus coding for a putative acetyl-CoA acetyltransferase. To elucidate atomic details, we determined crystal structures of AibR in the apo, the IV-CoA- and the IV-CoA-DNA-bound state to 1.7 Å, 2.35 Å and 2.92 Å, respectively. IV-CoA induces partial unfolding of an α-helix, which allows sequence-specific interactions between AibR and its operator. This study provides insights into AibR-mediated regulation and shows that AibR functions in an unusual TetR-like manner by blocking transcription not in the ligand-free but in the effector-bound state.
en
The AibR-isovaleryl coenzyme A regulator and its DNA binding site - a model for the regulation of alternative de novo isovaleryl coenzyme A biosynthesis in Myxococcus xanthus.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620688/1/Bock%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6208062019-08-30T11:28:49Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Thänert, Robert
author
Goldmann, Oliver
author
Beineke, Andreas
author
Medina, Eva
department
Helmholtz Centre for infection research. Inhoffenstr. 7. 38124 Braunschweig, Germany.
2017-02-03T13:10:34Z
2017-02-03
Host-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection 2017, 8:14268 Nature Communications
2041-1723
10.1038/ncomms14268
http://hdl.handle.net/10033/620806
Nature Communications
Host-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6208382019-08-30T11:29:17Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Thänert, Robert
author
Goldmann, Oliver
author
Beineke, Andreas
author
Medina, Eva
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-02-22T15:41:29Z
2017-02-03
Host-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection. 2017, 8:14268 Nat Commun
2041-1723
28155859
10.1038/ncomms14268
http://hdl.handle.net/10033/620838
Nature communications
The rise of antibiotic resistance calls for alternative strategies to treat bacterial infections. One attractive strategy is to directly target bacterial virulence factors with anti-virulence drugs. The expression of virulence traits by pathogens is, however, not constitutive but rather induced by the level of stress encountered within the host. Here we use dual RNA sequencing (RNA-seq) to show that intrinsic variability in the level of host resistance greatly affects the pathogen's transcriptome in vivo. Through analysis of the transcriptional profiles of host and pathogen during Staphylococcus aureus infection of two mouse strains, shown to be susceptible (A/J) or resistant (C57BL/6) to the pathogen, we demonstrate that the expression of virulence factors is dependent on the encountered host resistance. We furthermore provide evidence that this dependence strongly influences the efficacy of anti-virulence strategies, highlighting a potential limitation for the implementation of these strategies.
en
Host-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6208472019-08-30T11:27:16Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Awal, Ram Prasad
author
Garcia, Ronald
author
Gemperlein, Katja
author
Wink, Joachim
author
Kunwar, Bikram
author
Parajuli, Niranjan
author
Müller, Rolf
department
Helmholtz-Institue für Pharmazeutische Forschung Saarland (HIPS), Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-03-06T13:43:45Z
2017-01-28
Vitiosangium cumulatum gen. nov., sp. nov. and Vitiosangium subalbum sp. nov., novel soil myxobacteria from Nepal , and emended descriptions of genus Archangium and Angiococcus, and of Cystobacteraceae family. 2017 Int. J. Syst. Evol. Microbiol.
1466-5034
28141508
10.1099/ijsem.0.001829
http://hdl.handle.net/10033/620847
International journal of systematic and evolutionary microbiology
Bacterial strains designated MCy10943T and MCy10944T were isolated in 2014 from dried Nepalese soil samples collected in 2013 from Phukot, Kalikot, Western Nepal and Godawari, Lalitpur, Central Nepal. The novel organisms showed typical myxobacterial growth characteristics which include swarming colony and fruiting body formation on solid surfaces, and a predatory ability to lyse microorganisms. The strains were aerobic, mesophilic, chemoheterotrophic and showed resistance to various antibiotics. The major cellular fatty acids common to both organisms were C17:0 2-OH, iso-C15:0, C16:1 and iso-C17:0. The G + C content of the genomic DNA was 72-75 mol %. Phylogenetic analysis showed that the strains belong to the family Cystobacteraceae, suborder Cystobacterineae, order Myxococcales. The 16S rRNA gene sequences of both strains showed 97-98 % similarity to Archangium gephyra DSM 2261T, Cystobacter violaceus DSM 14727T, and 96.7-97 % to Cystobacter fuscus DSM 2262T and Angiococcus disciformis DSM 52716T. Polyphasic taxonomic characterisation suggested that strains MCy10943T and MCy10944T represent two distinct species of a novel genus, for which the names Vitiosangium cumulatum and Vitiosangium subalbum are proposed. The type strain of Vitiosangium cumulatum is MCy10943T (=DSM 102952T =NCCB 100600T) while for Vitiosangium subalbum is MCy10944T (=DSM 102953T =NCCB 100601T). In addition, the genera Archangium and Angiococcus, and the family Cystobacteraceae is herewith emended.
en
Vitiosangium cumulatum gen. nov., sp. nov. and Vitiosangium subalbum sp. nov., novel soil myxobacteria from Nepal , and emended descriptions of genus Archangium and Angiococcus, and of Cystobacteraceae family.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620847/1/Awal%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6208482019-08-30T11:34:22Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Thomas, Lea
author
Rao, Zhigang
author
Gerstmeier, Jana
author
Raasch, Martin
author
Weinigel, Christina
author
Rummler, Silke
author
Menche, Dirk
author
Müller, Rolf
author
Pergola, Carlo
author
Mosig, Alexander
author
Werz, Oliver
department
Helmholtz-Institue für Pharmazeutische Forschung Saarland (HIPS), Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-03-06T14:15:51Z
2017-02-09
Selective upregulation of TNFα expression in classically-activated human monocyte-derived macrophages (M1) through pharmacological interference with V-ATPase. 2017 Biochem. Pharmacol.
1873-2968
28189727
10.1016/j.bcp.2017.02.004
http://hdl.handle.net/10033/620848
Biochemical pharmacology
Pharmacological interference with vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, is considered a potential strategy for cancer therapy. Macrophages are critically involved in tumor progression and may occur as pro-tumoral M2 phenotype, whereas classically-activated M1 can inhibit tumor development for example by releasing tumor-suppressing molecules, including tumor necrosis factor (TNF)α. Here, we show that targeting V-ATPase by selective inhibitors such as archazolid upregulates the expression and secretion of TNFα in lipopolysaccharide (LPS)- or LPS/interferon (INF)γ-activated M1-like macrophages derived from human blood monocytes. In contrast, archazolid failed to elevate TNFα production from uncommitted (M0) or interleukin (IL)-4-treated M2-like macrophages. Secretion of other relevant cytokines (i.e., IL-1β, IL-6, IL-10) or chemokines (i.e. IL-8 and monocyte chemotactic protein-1) from M1 was not affected by archazolid. Though V-ATPase inhibitors elevated the lysosomal pH in M1 comparable to chloroquine or ammonium chloride, the latter agents suppressed TNFα secretion. Archazolid selectively increased TNFα mRNA levels, which was abolished by dexamethasone. Interestingly, archazolid enhanced the phosphorylation and nuclear translocation of the p65 subunit of NFκB and stimulated phosphorylation of SAPK/JNK. In a microfluidically-supported human tumor biochip model, archazolid-treated M1 significantly reduced tumor cell viability. Together, our data show that V-ATPase inhibition selectively upregulates TNFα production in classically-activated macrophages along with NFκB and SAPK/JNK activation. Such increased TNFα release caused by V-ATPase inhibitors may contribute to tumor suppression in addition to direct targeting cancer cells.
en
Selective upregulation of TNFα expression in classically-activated human monocyte-derived macrophages (M1) through pharmacological interference with V-ATPase.
Article
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https://hzi.openrepository.com/bitstream/10033/620848/1/Thomas%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6208732019-08-30T11:33:51Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Schmidt, Witali
author
Jones, Peter
author
Herrmann, Jennifer
author
Müller, Rolf
author
Schulz, Stefan
department
Helmholtz-Institut für Pharmaceutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
institution
Institute of Organic Chemistry, Technische Universität Braunschweig
institution
Institute of Inorganic and Analytical Chemistry, Technische Universität Braunschweig
institution
Department Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, Saarland University
institution
Department Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, Saarland University
institution
Institute of Organic Chemistry, Technische Universität Braunschweig
2017-03-28T14:15:15Z
2016-11-18
An Unprecedented Octahydro-3H-oxeto[2,3,4-ij]isochromene Ring System Formed by a Trichloromethyl-Anion-Induced Reaction Cascade 2016, 28 (04):467 Synlett
0936-5214
10.1055/s-0036-1588917
http://hdl.handle.net/10033/620873
Synlett
An Unprecedented Octahydro-3H-oxeto[2,3,4-ij]isochromene Ring System Formed by a Trichloromethyl-Anion-Induced Reaction Cascade
Article
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https://hzi.openrepository.com/bitstream/10033/620873/1/Schmidt%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6209272019-08-30T11:35:39Zcom_10033_311308com_10033_620618col_10033_620619col_10033_620619col_10033_559591
Helmholtz Zentrum für Infektionsforschung Repository
author
Bock, Tobias
author
Kasten, Janin
author
Müller, Rolf
author
Blankenfeldt, Wulf
department
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-05-22T14:01:14Z
2016-07-01
Crystal Structure of the HMG-CoA Synthase MvaS from the Gram-Negative Bacterium Myxococcus xanthus. 2016, 17 (13):1257-62 Chembiochem
1439-7633
27124816
10.1002/cbic.201600070
http://hdl.handle.net/10033/620927
Chembiochem : a European journal of chemical biology
A critical step in bacterial isoprenoid production is the synthesis of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) catalyzed by HMG-CoA synthase (HMGCS). In myxobacteria, this enzyme is also involved in a recently discovered alternative and acetyl-CoA-dependent isovaleryl CoA biosynthesis pathway. Here we present crystal structures of MvaS, the HMGCS from Myxococcus xanthus, in complex with CoA and acetylated active site Cys115, with the second substrate acetoacetyl CoA and with the product of the condensation reaction, 3-hydroxy-3-methylglutaryl CoA. With these structures, we show that MvaS uses the common HMGCS enzymatic mechanism and provide evidence that dimerization plays a role in the formation and stability of the active site. Overall, MvaS shows features typical of the eukaryotic HMGCS and exhibits differences from homologues from Gram-positive bacteria. This study provides insights into myxobacterial alternative isovaleryl CoA biosynthesis and thereby extends the toolbox for the biotechnological production of renewable fuel and chemicals.
en
Crystal Structure of the HMG-CoA Synthase MvaS from the Gram-Negative Bacterium Myxococcus xanthus.
Article
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oai:repository.helmholtz-hzi.de:10033/6209372019-08-30T11:34:22Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Tokovenko, Bogdan
author
Rückert, Christian
author
Kalinowski, Jörn
author
Mohammadipanah, Fatemeh
author
Wink, Joachim
author
Rosenkränzer, Birgit
author
Myronovskyi, Maksym
author
Luzhetskyy, Andriy N
department
Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-06-09T09:46:10Z
2017-05-18
Complete Draft Genome Sequence of the Actinobacterium Nocardiopsis sinuspersici UTMC102 (DSM 45277(T)), Which Produces Serine Protease. 2017, 5 (20) Genome Announc
28522715
10.1128/genomeA.00362-17
http://hdl.handle.net/10033/620937
Genome announcements
The genome sequence of alkalohalophilic actinobacterium Nocardiopsis sinuspersici UTMC102 is provided. N. sinuspersici UTMC102 produces a highly active serine alkaline protease, and contains at least 11 gene clusters encoding the biosynthesis of secondary metabolites. The N. sinuspersici UTMC102 genome was assembled into a single chromosomal scaffold.
en
Complete Draft Genome Sequence of the Actinobacterium Nocardiopsis sinuspersici UTMC102 (DSM 45277(T)), Which Produces Serine Protease.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620937/1/-Tokovenko%20et%20al..pdf
File
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URL
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oai:repository.helmholtz-hzi.de:10033/6209642019-08-30T11:33:57Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Axenov-Gribanov, Denis V
author
Tokovenko, Bogdan T
author
Rebets, Yuriy V
author
Voytsekhovskaya, Irina V
author
Shatilina, Zhanna M
author
Protasov, Eugenii S
author
Luzhetskyy, Andriy N
author
Timofeyev, Maxim A
department
Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-06-21T08:03:29Z
2017-04-27
Draft Genome Sequence of Streptomyces sp. Strain IB2014011-1, Isolated from Trichoptera sp. Larvae of Lake Baikal. 2017, 5 (17) Genome Announc
28450500
10.1128/genomeA.00062-17
http://hdl.handle.net/10033/620964
Genome announcements
Unique ecosystems with specific environmental conditions have been proven to be a promising source for isolation of new actinobacterial strains. Ancient Lake Baikal is one of the greatest examples of an ecosystem with high species biodiversity and endemicity caused by long-lasting isolated evolution and stable environmental conditions. Herein we report the draft genome sequence of Streptomyces sp. strain IB2014011-1, which was isolated from insect Trichoptera sp. larvae collected at the bottom of Lake Baikal.
en
Draft Genome Sequence of Streptomyces sp. Strain IB2014011-1, Isolated from Trichoptera sp. Larvae of Lake Baikal.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620964/1/Axenov-Gribanov%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6209672019-08-30T11:34:22Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Koshla, Oksana
author
Lopatniuk, Maria
author
Rokytskyy, Ihor
author
Yushchuk, Oleksandr
author
Dacyuk, Yuriy
author
Fedorenko, Victor
author
Luzhetskyy, Andriy N
author
Ostash, Bohdan
department
Helmholtz Institut für phsarmazeutische Forschung Saarland (HIPS), Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-06-21T11:37:08Z
2017-05-20
Properties of Streptomyces albus J1074 mutant deficient in tRNA(Leu)UAA gene bldA. 2017 Arch. Microbiol.
1432-072X
28528473
10.1007/s00203-017-1389-7
http://hdl.handle.net/10033/620967
Archives of microbiology
Streptomyces albus J1074 is one of the most popular and convenient hosts for heterologous expression of gene clusters directing the biosynthesis of various natural metabolic products, such as antibiotics. This fuels interest in elucidation of genetic mechanisms that may limit secondary metabolism in J1074. Here, we report the generation and initial study of J1074 mutant, deficient in gene bldA for tRNA(Leu)UAA, the only tRNA capable of decoding rare leucyl TTA codon in Streptomyces. The bldA deletion in J1074 resulted in a highly conditional Bld phenotype, with depleted formation of aerial hyphae on certain solid media. In addition, bldA mutant of J1074 was unable to produce endogenous antibacterial compounds and two heterologous antibiotics, moenomycin and aranciamycin, whose biosynthesis is directed by TTA-containing genes. We have employed a new TTA codon-specific β-galactosidase reporter system to provide genetic evidence that J1074 bldA mutant is impaired in translation of TTA. In addition, we have discussed the possible reasons for differences in the phenotypes of bldA mutants described here and in previous studies, providing knowledge to study bldA-based regulation of antibiotic biosynthesis.
en
Properties of Streptomyces albus J1074 mutant deficient in tRNA(Leu)UAA gene bldA.
Article
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oai:repository.helmholtz-hzi.de:10033/6209992019-08-30T11:25:11Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Paulus, Constanze
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Nadmid, Suvd
author
Terekhova, Larisa P
author
Myronovskyi, Maksym
author
Zotchev, Sergey B
author
Rückert, Christian
author
Braig, Simone
author
Zahler, Stefan
author
Kalinowski, Jörn
author
Luzhetskyy, Andriy N
department
Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-07-05T14:47:26Z
2017-02-10
New natural products identified by combined genomics-metabolomics profiling of marine Streptomyces sp. MP131-18. 2017, 7:42382 Sci Rep
2045-2322
28186197
10.1038/srep42382
http://hdl.handle.net/10033/620999
Scientific reports
Marine actinobacteria are drawing more and more attention as a promising source of new natural products. Here we report isolation, genome sequencing and metabolic profiling of new strain Streptomyces sp. MP131-18 isolated from marine sediment sample collected in the Trondheim Fjord, Norway. The 16S rRNA and multilocus phylogenetic analysis showed that MP131-18 belongs to the genus Streptomyces. The genome of MP131-18 isolate was sequenced, and 36 gene clusters involved in the biosynthesis of 18 different types of secondary metabolites were predicted using antiSMASH analysis. The combined genomics-metabolics profiling of the strain led to the identification of several new biologically active compounds. As a result, the family of bisindole pyrroles spiroindimicins was extended with two new members, spiroindimicins E and F. Furthermore, prediction of the biosynthetic pathway for unusual α-pyrone lagunapyrone isolated from MP131-18 resulted in foresight and identification of two new compounds of this family - lagunapyrones D and E. The diversity of identified and predicted compounds from Streptomyces sp. MP131-18 demonstrates that marine-derived actinomycetes are not only a promising source of new natural products, but also represent a valuable pool of genes for combinatorial biosynthesis of secondary metabolites.
en
New natural products identified by combined genomics-metabolomics profiling of marine Streptomyces sp. MP131-18.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6210042019-08-30T11:31:23Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Pergola, Carlo
author
Schubert, Katrin
author
Pace, Simona
author
Ziereisen, Jana
author
Nikels, Felix
author
Scherer, Olga
author
Hüttel, Stephan
author
Zahler, Stefan
author
Vollmar, Angelika M
author
Weinigel, Christina
author
Rummler, Silke
author
Müller, Rolf
author
Raasch, Martin
author
Mosig, Alexander
author
Koeberle, Andreas
author
Werz, Oliver
department
Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-07-11T10:05:51Z
2017-01-30
Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy. 2017, 7:41434 Sci Rep
2045-2322
28134280
10.1038/srep41434
http://hdl.handle.net/10033/621004
Scientific reports
Tumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. Selective depletion or reprogramming of M2 may represent an innovative anti-cancer strategy. The actin cytoskeleton is central for cellular homeostasis and is targeted for anti-cancer chemotherapy. Here, we show that targeting G-actin nucleation using chondramide A (ChA) predominantly depletes human M2 while promoting the tumour-suppressive M1 phenotype. ChA reduced the viability of M2, with minor effects on M1, but increased tumour necrosis factor (TNF)α release from M1. Interestingly, ChA caused rapid disruption of dynamic F-actin filaments and polymerization of G-actin, followed by reduction of cell size, binucleation and cell division, without cellular collapse. In M1, but not in M2, ChA caused marked activation of SAPK/JNK and NFκB, with slight or no effects on Akt, STAT-1/-3, ERK-1/2, and p38 MAPK, seemingly accounting for the better survival of M1 and TNFα secretion. In a microfluidically-supported human tumour biochip model, circulating ChA-treated M1 markedly reduced tumour cell viability through enhanced release of TNFα. Together, ChA may cause an anti-tumoural microenvironment by depletion of M2 and activation of M1, suggesting induction of G-actin nucleation as potential strategy to target tumour-associated macrophages in addition to neoplastic cells.
en
Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy.
Article
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URL
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URL
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oai:repository.helmholtz-hzi.de:10033/6210252019-08-30T11:33:57Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Leech, John M
author
Lacey, Keenan A
author
Mulcahy, Michelle E
author
Medina, Eva
author
McLoughlin, Rachel M
2017-07-31T14:37:09Z
2017-03-15
IL-10 Plays Opposing Roles during Staphylococcus aureus Systemic and Localized Infections. 2017, 198 (6):2352-2365 J. Immunol.
1550-6606
28167629
10.4049/jimmunol.1601018
http://hdl.handle.net/10033/621025
Journal of immunology (Baltimore, Md. : 1950)
IL-10 is a potent anti-inflammatory mediator that plays a crucial role in limiting host immunopathology during bacterial infections by controlling effector T cell activation. Staphylococcus aureus has previously been shown to manipulate the IL-10 response as a mechanism of immune evasion during chronic systemic and biofilm models of infection. In the present study, we demonstrate divergent roles for IL-10 depending on the site of infection. During acute systemic S. aureus infection, IL-10 plays an important protective role and is required to prevent bacterial dissemination and host morbidity by controlling effector T cells and the associated downstream hyperactivation of inflammatory phagocytes, which are capable of host tissue damage. CD19(+)CD11b(+)CD5(+) B1a regulatory cells were shown to rapidly express IL-10 in a TLR2-dependent manner in response to S. aureus, and adoptive transfer of B1a cells was protective during acute systemic infection in IL-10-deficient hosts. In contrast, during localized s.c. infection, IL-10 production plays a detrimental role by facilitating bacterial persistence via the same mechanism of controlling proinflammatory T cell responses. Our findings demonstrate that induction of IL-10 has a major influence on disease outcome during acute S. aureus infection. Too much IL-10 at one end of the scale may suppress otherwise protective T cell responses, thus facilitating persistence of the bacteria, and at the other end, too little IL-10 may tend toward fatal host-mediated pathology through excessive activation of T cells and associated phagocyte-mediated damage.
en
IL-10 Plays Opposing Roles during Staphylococcus aureus Systemic and Localized Infections.
Article
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oai:repository.helmholtz-hzi.de:10033/6210722019-08-30T11:26:42Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Petković, Hrvoje
author
Lukežič, Tadeja
author
Šušković, Jagoda
department
Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-08-22T14:27:11Z
2017-03
Biosynthesis of Oxytetracycline by Streptomyces rimosus:
Past, Present and Future Directions in the Development
of Tetracycline Antibiotics. 2017, 55 (1):3-13 Food Technol. Biotechnol.
1330-9862
28559729
10.17113/ftb.55.01.17.4617
http://hdl.handle.net/10033/621072
Food technology and biotechnology
Natural tetracycline (TC) antibiotics were the first major class of therapeutics to earn the distinction of 'broad-spectrum antibiotics' and they have been used since the 1940s against a wide range of both Gram-positive and Gram-negative pathogens, mycoplasmas, intracellular chlamydiae, rickettsiae and protozoan parasites. The second generation of semisynthetic tetracyclines, such as minocycline and doxycycline, with improved antimicrobial potency, were introduced during the 1960s. Despite emerging resistance to TCs erupting during the 1980s, it was not until 2006, more than four decades later, that a third--generation TC, named tigecycline, was launched. In addition, two TC analogues, omadacycline and eravacycline, developed via (semi)synthetic and fully synthetic routes, respectively, are at present under clinical evaluation. Interestingly, despite very productive early work on the isolation of a Streptomyces aureofaciens mutant strain that produced 6-demethyl-7-chlortetracycline, the key intermediate in the production of second- and third-generation TCs, biosynthetic approaches in TC development have not been productive for more than 50 years. Relatively slow and tedious molecular biology approaches for the genetic manipulation of TC-producing actinobacteria, as well as an insufficient understanding of the enzymatic mechanisms involved in TC biosynthesis have significantly contributed to the low success of such biosynthetic engineering efforts. However, new opportunities in TC drug development have arisen thanks to a significant progress in the development of affordable and versatile biosynthetic engineering and synthetic biology approaches, and, importantly, to a much deeper understanding of TC biosynthesis, mostly gained over the last two decades.
en
Biosynthesis of Oxytetracycline by Streptomyces rimosus:
Past, Present and Future Directions in the Development
of Tetracycline Antibiotics.
Article
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oai:repository.helmholtz-hzi.de:10033/6210922019-08-30T11:27:16Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Bartel, Karin
author
Winzi, Maria
author
Ulrich, Melanie
author
Koeberle, Andreas
author
Menche, Dirk
author
Werz, Oliver
author
Müller, Rolf
author
Guck, Jochen
author
Vollmar, Angelika M
author
von Schwarzenberg, Karin
department
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-09-05T13:22:21Z
2017-02-07
V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy. 2017, 8 (6):9476-9487 Oncotarget
1949-2553
28036299
10.18632/oncotarget.14339
http://hdl.handle.net/10033/621092
Oncotarget
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide and the third leading cause of cancer-related death. However, therapy options are limited leaving an urgent need to develop new strategies. Currently, targeting cancer cell lipid and cholesterol metabolism is gaining interest especially regarding HCC. High cholesterol levels support proliferation, membrane-related mitogenic signaling and increase cell softness, leading to tumor progression, malignancy and invasive potential. However, effective ways to target cholesterol metabolism for cancer therapy are still missing. The V-ATPase inhibitor archazolid was recently shown to interfere with cholesterol metabolism. In our study, we report a novel therapeutic potential of V-ATPase inhibition in HCC by altering the mechanical phenotype of cancer cells leading to reduced proliferative signaling. Archazolid causes cellular depletion of free cholesterol leading to an increase in cell stiffness and membrane polarity of cancer cells, while hepatocytes remain unaffected. The altered membrane composition decreases membrane fluidity and leads to an inhibition of membrane-related Ras signaling resulting decreased proliferation in vitro and in vivo. V-ATPase inhibition represents a novel link between cell biophysical properties and proliferative signaling selectively in malignant HCC cells, providing the basis for an attractive and innovative strategy against HCC.
en
V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6211022019-08-30T11:33:57Zcom_10033_620857com_10033_620618col_10033_620858col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Beckmann, Amelie
author
Hüttel, Stephan
author
Schmitt, Viktoria
author
Müller, Rolf
author
Stadler, Marc
department
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-09-11T12:23:25Z
2017-08-17
Optimization of the biotechnological production of a novel class of anti-MRSA antibiotics from Chitinophaga sancti. 2017, 16 (1):143 Microb. Cell Fact.
1475-2859
28818083
10.1186/s12934-017-0756-z
http://hdl.handle.net/10033/621102
Microbial cell factories
Recently, the discovery of the elansolids, a group of macrolides, was reported. The molecules show activity against methicillin-resistant Staphylococcus aureus as well as other gram-positive organisms. This fact renders those substances a promising starting point for future chemical development. The active atropisomers A1/A2 are formed by macrolactonization of the biosynthesis product A3 but are prone to ring opening and subsequent formation of several unwanted side products. Recently it could be shown that addition of different nucleophiles to culture extracts of Chitinophaga sancti enable the formation of new stable elansolid derivatives. Furthermore, addition of such a nucleophile directly into the culture led exclusively to formation of a single active elansolid derivative. Due to low product yields, methods for production of gram amounts of these molecules have to be established to enable further development of this promising compound class.
en
Optimization of the biotechnological production of a novel class of anti-MRSA antibiotics from Chitinophaga sancti.
Article
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oai:repository.helmholtz-hzi.de:10033/6211182019-08-30T11:37:24Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Bilyk, Bohdan
author
Horbal, Liliya
author
Luzhetskyy, Andriy N
department
Helmholz-Institut für pharmazeutische Forschung , Josef-Schneider-Straße2,97080 Würzburg, Germany.
2017-09-25T12:13:33Z
2017-01-04
Chromosomal position effect influences the heterologous expression of genes and biosynthetic gene clusters in Streptomyces albus J1074. 2017, 16 (1):5 Microb. Cell Fact.
1475-2859
28052753
10.1186/s12934-016-0619-z
http://hdl.handle.net/10033/621118
Microbial cell factories
Efforts to construct the Streptomyces host strain with enhanced yields of heterologous product have focussed mostly on engineering of primary metabolism and/or the deletion of endogenous biosynthetic gene clusters. However, other factors, such as chromosome compactization, have been shown to have a significant influence on gene expression levels in bacteria and fungi. The expression of genes and biosynthetic gene clusters may vary significantly depending on their location within the chromosome. Little is known about the position effect in actinomycetes, which are important producers of various industrially relevant bioactive molecules.
en
Chromosomal position effect influences the heterologous expression of genes and biosynthetic gene clusters in Streptomyces albus J1074.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621118/1/Bilyk%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6211212019-08-30T11:27:16Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Ahmed, Yousra
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Brötz, Elke
author
Luzhetskyy, Andriy N
department
Helmholtz-Institut für pharmazeutische Forschung Saarland,Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-09-26T09:34:57Z
2017-08-29
Identification of butenolide regulatory system controlling secondary metabolism in Streptomyces albus J1074. 2017, 7 (1):9784 Sci Rep
2045-2322
28852167
10.1038/s41598-017-10316-y
http://hdl.handle.net/10033/621121
Scientific reports
A large majority of genome-encrypted chemical diversity in actinobacteria remains to be discovered, which is related to the low level of secondary metabolism genes expression. Here, we report the application of a reporter-guided screening strategy to activate cryptic polycyclic tetramate macrolactam gene clusters in Streptomyces albus J1074. The analysis of the S. albus transcriptome revealed an overall low level of secondary metabolism genes transcription. Combined with transposon mutagenesis, reporter-guided screening resulted in the selection of two S. albus strains with altered secondary metabolites production. Transposon insertion in the most prominent strain, S. albus ATGSal2P2::TN14, was mapped to the XNR_3174 gene encoding an unclassified transcriptional regulator. The mutant strain was found to produce the avenolide-like compound butenolide 4. The deletion of the gene encoding a putative acyl-CoA oxidase, an orthologue of the Streptomyces avermitilis avenolide biosynthesis enzyme, in the S. albus XNR_3174 mutant caused silencing of secondary metabolism. The homologues of XNR_3174 and the butenolide biosynthesis genes were found in the genomes of multiple Streptomyces species. This result leads us to believe that the discovered regulatory elements comprise a new condition-dependent system that controls secondary metabolism in actinobacteria and can be manipulated to activate cryptic biosynthetic pathways.
en
openAccess
Identification of butenolide regulatory system controlling secondary metabolism in Streptomyces albus J1074.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621121/1/Ahmed%20and%20Luzhetskyy.pdf
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oai:repository.helmholtz-hzi.de:10033/6211362019-08-30T11:27:16Zcom_10033_311624com_10033_6839com_10033_620618col_10033_311625col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Rox, Katharina
author
Jansen, Rolf
author
Loof, Torsten G.
author
Gillen, Christine M.
author
Bernecker, Steffen
author
Walker, Mark J.
author
Chhatwal, Gursharan Singh
author
Müller, Rolf
department
Helmholtz-Institut für pharmazeutische Forschung Saarland,Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-10-12T09:13:35Z
2017-09-18
Linoleic and palmitoleic acid block streptokinase-mediated plasminogen activation and reduce severity of invasive group A streptococcal infection 2017, 7 (1) Scientific Reports
2045-2322
10.1038/s41598-017-11276-z
http://hdl.handle.net/10033/621136
Scientific Reports
In contrast to mild infections of Group A Streptococcus (GAS) invasive infections of GAS still pose a serious health hazard: GAS disseminates from sterile sites into the blood stream or deep tissues and causes sepsis or necrotizing fasciitis. In this case antibiotics do not provide an effective cure as the bacteria are capable to hide from them very quickly. Therefore, new remedies are urgently needed. Starting from a myxobacterial natural products screening campaign, we identified two fatty acids isolated from myxobacteria, linoleic and palmitoleic acid, specifically blocking streptokinase-mediated activation of plasminogen and thereby preventing streptococci from hijacking the host’s plasminogen/plasmin system. This activity is not inherited by other fatty acids such as oleic acid and is not attributable to the killing of streptococci. Moreover, both fatty acids are superior in their inhibitory properties compared to two clinically used drugs (tranexamic or ε-amino caproic acid) as they show 500–1000 fold lower IC50 values. Using a humanized plasminogen mouse model mimicking the clinical situation of a local GAS infection that becomes systemic, we demonstrate that these fatty acids ameliorate invasive GAS infection significantly. Consequently, linoleic and palmitoleic acid are possible new options to combat GAS invasive diseases.
Linoleic and palmitoleic acid block streptokinase-mediated plasminogen activation and reduce severity of invasive group A streptococcal infection
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621136/1/Rox%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6211512019-08-30T11:33:57Zcom_10033_620636com_10033_620644com_10033_620618col_10033_620619col_10033_620638col_10033_620647
Helmholtz Zentrum für Infektionsforschung Repository
author
Donner, Jannik
author
Reck, Michael
author
Bunk, Boyke
author
Jarek, Michael
author
App, Constantin Benjamin
author
Meier-Kolthoff, Jan P
author
Overmann, Jörg
author
Müller, Rolf
author
Kirschning, Andreas
author
Wagner-Döbler, Irene
department
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr, 7,38124 Braunschweig, Germany.
2017-11-01T12:55:13Z
2017-11-01
The Biofilm Inhibitor Carolacton Enters Gram-Negative Cells: Studies Using a TolC-Deficient Strain of Escherichia coli., 2 (5) mSphere
2379-5042
28959742
10.1128/mSphereDirect.00375-17
http://hdl.handle.net/10033/621151
mSphere
The myxobacterial secondary metabolite carolacton inhibits growth of Streptococcus pneumoniae and kills biofilm cells of the caries- and endocarditis-associated pathogen Streptococcus mutans at nanomolar concentrations. Here, we studied the response to carolacton of an Escherichia coli strain that lacked the outer membrane protein TolC. Whole-genome sequencing of the laboratory E. coli strain TolC revealed the integration of an insertion element, IS5, at the tolC locus and a close phylogenetic relationship to the ancient E. coli K-12. We demonstrated via transcriptome sequencing (RNA-seq) and determination of MIC values that carolacton penetrates the phospholipid bilayer of the Gram-negative cell envelope and inhibits growth of E. coli TolC at similar concentrations as for streptococci. This inhibition is completely lost for a C-9 (R) epimer of carolacton, a derivative with an inverted stereocenter at carbon atom 9 [(S) → (R)] as the sole difference from the native molecule, which is also inactive in S. pneumoniae and S. mutans, suggesting a specific interaction of native carolacton with a conserved cellular target present in bacterial phyla as distantly related as Firmicutes and Proteobacteria. The efflux pump inhibitor (EPI) phenylalanine arginine β-naphthylamide (PAβN), which specifically inhibits AcrAB-TolC, renders E. coli susceptible to carolacton. Our data indicate that carolacton has potential for use in antimicrobial chemotherapy against Gram-negative bacteria, as a single drug or in combination with EPIs. Strain E. coli TolC has been deposited at the DSMZ; together with the associated RNA-seq data and MIC values, it can be used as a reference during future screenings for novel bioactive compounds. IMPORTANCE The emergence of pathogens resistant against most or all of the antibiotics currently used in human therapy is a global threat, and therefore the search for antimicrobials with novel targets and modes of action is of utmost importance. The myxobacterial secondary metabolite carolacton had previously been shown to inhibit biofilm formation and growth of streptococci. Here, we investigated if carolacton could act against Gram-negative bacteria, which are difficult targets because of their double-layered cytoplasmic envelope. We found that the model organism Escherichia coli is susceptible to carolacton, similar to the Gram-positive Streptococcus pneumoniae, if its multidrug efflux system AcrAB-TolC is either inactivated genetically, by disruption of the tolC gene, or physiologically by coadministering an efflux pump inhibitor. A carolacton epimer that has a different steric configuration at carbon atom 9 is completely inactive, suggesting that carolacton may interact with the same molecular target in both Gram-positive and Gram-negative bacteria.
en
The Biofilm Inhibitor Carolacton Enters Gram-Negative Cells: Studies Using a TolC-Deficient Strain of Escherichia coli.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621151/1/Donner%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6211562019-08-30T11:35:39Zcom_10033_620618col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Goldmann, Oliver
author
Beineke, Andreas
author
Medina, Eva
department
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunchweig, Germany.
2017-11-02T15:23:27Z
2017-09-23
Identification of a novel subset of myeloid-derived suppressor cells during chronic staphylococcal infection that resembles immature eosinophils. 2017 J. Infect. Dis.
1537-6613
29029332
10.1093/infdis/jix494
http://hdl.handle.net/10033/621156
The Journal of infectious diseases
We have previously reported that myeloid-derived suppressor cells (MDSC), which are a heterogeneous population of immunosuppressive immature myeloid cells, expanded during chronic Staphylococcus aureus infection and promoted bacterial persistence by inhibiting effector T cells. Two major MDSC subsets including monocytic MDSCs (M-MDSC) and granulocytic MDSCs (G-MDSC) have been described to date. Here, we identified a new subset of MDSC (Eo-MDSC) in S. aureus-infected mice that phenotypically resembles eosinophils. Eo-MDSC exhibit eosinophilic cytoplasmic granules and express CD11b, the eosinophil marker Syglec-F, variable levels of CCR3 and low levels of IL-5R. Furthermore, Eo-MDSC accumulated at the site of infection and exerted a potent immunosuppressive effect on T cell responses that was mediated by nitric oxide-dependent depletion of L-arginine. Increased in the number of Eo-MDSC by adoptive transfer caused a significant exacerbation of infection in S. aureus-infected mice. This study sheds new light on the heterogeneity and complexity of MDSC during chronic infection.
en
Identification of a novel subset of myeloid-derived suppressor cells during chronic staphylococcal infection that resembles immature eosinophils.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621156/1/Goldmann%2c%20Beineke%20and%20Medina.pdf
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oai:repository.helmholtz-hzi.de:10033/6211842019-08-30T11:25:11Zcom_10033_620533com_10033_311308com_10033_620618col_10033_620534col_10033_620619col_10033_559591
Helmholtz Zentrum für Infektionsforschung Repository
author
Lukat, Peer
author
Katsuyama, Yohei
author
Wenzel, Silke
author
Binz, Tina
author
König, Claudia
author
Blankenfeldt, Wulf
author
Brönstrup, Mark
author
Müller, Rolf
department
Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-11-27T15:04:00Z
2017-11-01
Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity. 2017, 8 (11):7521-7527 Chem Sci
2041-6520
29163906
10.1039/c7sc02622f
http://hdl.handle.net/10033/621184
Chemical science
Griselimycins (GMs) are depsidecapeptides with superb anti-tuberculosis activity. They contain up to three (2S,4R)-4-methyl-prolines (4-MePro), of which one blocks oxidative degradation and increases metabolic stability in animal models. The natural congener with this substitution is only a minor component in fermentation cultures. We showed that this product can be significantly increased by feeding the reaction with 4-MePro and we investigated the molecular basis of 4-MePro biosynthesis and incorporation. We identified the GM biosynthetic gene cluster as encoding a nonribosomal peptide synthetase and a sub-operon for 4-MePro formation. Using heterologous expression, gene inactivation, and in vitro experiments, we showed that 4-MePro is generated by leucine hydroxylation, oxidation to an aldehyde, and ring closure with subsequent reduction. The crystal structures of the leucine hydroxylase GriE have been determined in complex with substrates and products, providing insight into the stereospecificity of the reaction.
en
Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity.
Article
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oai:repository.helmholtz-hzi.de:10033/6211902019-08-30T11:36:32Zcom_10033_620644com_10033_620618col_10033_620619col_10033_620647
Helmholtz Zentrum für Infektionsforschung Repository
author
Fu, Chengzhang
author
Sikandar, Asfandyar
author
Donner, Jannik
author
Zaburannyi, Nestor
author
Herrmann, Jennifer
author
Reck, Michael
author
Wagner-Döbler, Irene
author
Koehnke, Jesko
author
Müller, Rolf
department
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124Braunschweig, Germany.
2017-12-01T10:57:05Z
2017-11-16
The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD. 2017, 8 (1):1529 Nat Commun
2041-1723
29142318
10.1038/s41467-017-01671-5
http://hdl.handle.net/10033/621190
Nature communications
The natural product carolacton is a macrolide keto-carboxylic acid produced by the myxobacterium Sorangium cellulosum, and was originally described as an antibacterial compound. Here we show that carolacton targets FolD, a key enzyme from the folate-dependent C1 metabolism. We characterize the interaction between bacterial FolD and carolacton biophysically, structurally and biochemically. Carolacton binds FolD with nanomolar affinity, and the crystal structure of the FolD-carolacton complex reveals the mode of binding. We show that the human FolD orthologs, MTHFD1 and MTHFD2, are also inhibited in the low nM range, and that micromolar concentrations of carolacton inhibit the growth of cancer cell lines. As mitochondrial MTHFD2 is known to be upregulated in cancer cells, it may be possible to use carolacton as an inhibitor tool compound to assess MTHFD2 as an anti-cancer target.
en
The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621190/1/Fu%20et%20al.pdf
File
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URL
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oai:repository.helmholtz-hzi.de:10033/6212122019-08-30T11:34:22Zcom_10033_620656com_10033_620618col_10033_620658col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Wagner, Stefanie
author
Hauck, Dirk
author
Hoffmann, Michael
author
Sommer, Roman
author
Joachim, Ines
author
Müller, Rolf
author
Imberty, Anne
author
Varrot, Annabelle
author
Titz, Alexander
department
HIPS, Helmholtz-Institut für pharmazeutische Forchung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-12-20T10:44:14Z
2017-09-28
Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging. 2017 Angew. Chem. Int. Ed. Engl.
1521-3773
28960731
10.1002/anie.201709368
http://hdl.handle.net/10033/621212
Angewandte Chemie (International ed. in English)
Biofilm formation by pathogenic bacteria is a hallmark of chronic infections. In many cases, lectins play key roles in establishing biofilms. The pathogen Pseudomonas aeruginosa often exhibiting various drug resistances employs its lectins LecA and LecB as virulence factors and biofilm building blocks. Therefore, inhibition of the function of these proteins is thought to have potential in developing "pathoblockers" preventing biofilm formation and virulence. A covalent lectin inhibitor specific to a carbohydrate binding site is described for the first time. Its application in the LecA-specific in vitro imaging of biofilms formed by P. aeruginosa is also reported.
en
Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6212152019-08-30T11:31:49Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Corr, M J
author
Sharma, S V
author
Pubill-Ulldemolins, C
author
Bown, R T
author
Poirot, P
author
Smith, D R M
author
Cartmell, C
author
Abou Fayad, A
author
Goss, R J M
department
Hel,holtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2018-01-02T09:25:10Z
2017-03-01
Sonogashira diversification of unprotected halotryptophans, halotryptophan containing tripeptides; and generation of a new to nature bromo-natural product and its diversification in water. 2017, 8 (3):2039-2046 Chem Sci
2041-6520
28451322
10.1039/c6sc04423a
http://hdl.handle.net/10033/621215
Chemical science
The blending together of synthetic chemistry with natural product biosynthesis represents a potentially powerful approach to synthesis; to enable this, further synthetic tools and methodologies are needed. To this end, we have explored the first Sonogashira cross-coupling to halotryptophans in water. Broad reaction scope is demonstrated and we have explored the limits of the scope of the reaction. We have demonstrated this methodology to work excellently in the modification of model tripeptides. Furthermore, through precursor directed biosynthesis, we have generated for the first time a new to nature brominated natural product bromo-cystargamide, and demonstrated the applicability of our reaction conditions to modify this novel metabolite.
en
openAccess
Sonogashira diversification of unprotected halotryptophans, halotryptophan containing tripeptides; and generation of a new to nature bromo-natural product and its diversification in water.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6212172019-08-30T11:31:23Zcom_10033_338554com_10033_620618col_10033_621787col_10033_620621
Helmholtz Zentrum für Infektionsforschung Repository
author
Bergmann, Simone
author
Eichhorn, Inga
author
Kohler, Thomas P
author
Hammerschmidt, Sven
author
Goldmann, Oliver
author
Rohde, M
author
Fulde, Marcus
department
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2018-01-02T14:17:40Z
2017
SCM, the M Protein of Streptococcus canis Binds Immunoglobulin G. 2017, 7:80 Front Cell Infect Microbiol
2235-2988
28401063
10.3389/fcimb.2017.00080
http://hdl.handle.net/10033/621217
Frontiers in cellular and infection microbiology
The M protein of Streptococcus canis (SCM) is a virulence factor and serves as a surface-associated receptor with a particular affinity for mini-plasminogen, a cleavage product of the broad-spectrum serine protease plasmin. Here, we report that SCM has an additional high-affinity immunoglobulin G (IgG) binding activity. The ability of a particular S. canis isolate to bind to IgG significantly correlates with a scm-positive phenotype, suggesting a dominant role of SCM as an IgG receptor. Subsequent heterologous expression of SCM in non-IgG binding S. gordonii and Western Blot analysis with purified recombinant SCM proteins confirmed its IgG receptor function. As expected for a zoonotic agent, the SCM-IgG interaction is species-unspecific, with a particular affinity of SCM for IgGs derived from human, cats, dogs, horses, mice, and rabbits, but not from cows and goats. Similar to other streptococcal IgG-binding proteins, the interaction between SCM and IgG occurs via the conserved Fc domain and is, therefore, non-opsonic. Interestingly, the interaction between SCM and IgG-Fc on the bacterial surface specifically prevents opsonization by C1q, which might constitute another anti-phagocytic mechanism of SCM. Extensive binding analyses with a variety of different truncated SCM fragments defined a region of 52 amino acids located in the central part of the mature SCM protein which is important for IgG binding. This binding region is highly conserved among SCM proteins derived from different S. canis isolates but differs significantly from IgG-Fc receptors of S. pyogenes and S. dysgalactiae sub. equisimilis, respectively. In summary, we present an additional role of SCM in the pathogen-host interaction of S. canis. The detailed analysis of the SCM-IgG interaction should contribute to a better understanding of the complex roles of M proteins in streptococcal pathogenesis.
en
SCM, the M Protein of Streptococcus canis Binds Immunoglobulin G.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6212222019-08-30T11:25:43Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Hamed, Mostafa M
author
Darwish, Sarah S
author
Herrmann, Jennifer
author
Abadi, Ashraf H
author
Engel, Matthias
department
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1,66123 Saarbrücken, Germany.
2018-01-03T13:50:53Z
2017-04-13
First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents. 2017, 60 (7):2853-2868 J. Med. Chem.
1520-4804
28291344
10.1021/acs.jmedchem.6b01774
http://hdl.handle.net/10033/621222
Journal of medicinal chemistry
The activation of the NF-κB transcription factor is a major adaptive response induced upon treatment with EGFR kinase inhibitors, leading to the emergence of resistance in nonsmall cell lung cancer and other tumor types. To suppress this survival mechanism, we developed new thiourea quinazoline derivatives that are dual inhibitors of both EGFR kinase and the NF-κB activity. Optimization of the hit compound, identified in a NF-κB reporter gene assay, led to compound 9b, exhibiting a cellular IC50 for NF-κB inhibition of 0.3 μM while retaining a potent EGFR kinase inhibition (IC50 = 60 nM). The dual inhibitors showed a higher potency than gefitinib to inhibit cell growth of EGFR-overexpressing tumor cell lines in vitro and in a xenograft model in vivo, while no signs of toxicity were observed. An investigation of the molecular mechanism of NF-κB suppression revealed that the dual inhibitors depleted the transcriptional coactivator CREB-binding protein from the NF-κB complex in the nucleus.
en
First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621222/1/Hamed%20et%20al_main_final.pdf
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oai:repository.helmholtz-hzi.de:10033/6212312019-08-30T11:34:48Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Wu, Hang
author
Wang, Yansheng
author
Yuan, Li
author
Mao, Yongrong
author
Wang, Weiwei
author
Zhu, Lin
author
Wu, Panpan
author
Fu, Chengzhang
author
Müller, Rolf
author
Weaver, David T
author
Zhang, Lixin
author
Zhang, Buchang
department
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1,66123 Saarbrücken, Germany.
2018-01-11T10:02:26Z
2016-03
Inactivation of SACE_3446, a TetR family transcriptional regulator, stimulates erythromycin production in Saccharopolyspora erythraea. 2016, 1 (1):39-46 Synth Syst Biotechnol
2405-805X
29062926
10.1016/j.synbio.2016.01.004
http://hdl.handle.net/10033/621231
Synthetic and systems biotechnology
Erythromycin A is a widely used antibiotic produced by Saccharopolyspora erythraea; however, its biosynthetic cluster lacks a regulatory gene, limiting the yield enhancement via regulation engineering of S. erythraea. Herein, six TetR family transcriptional regulators (TFRs) belonging to three genomic context types were individually inactivated in S. erythraea A226, and one of them, SACE_3446, was proved to play a negative role in regulating erythromycin biosynthesis. EMSA and qRT-PCR analysis revealed that SACE_3446 covering intact N-terminal DNA binding domain specifically bound to the promoter regions of erythromycin biosynthetic gene eryAI, the resistant gene ermE and the adjacent gene SACE_3447 (encoding a long-chain fatty-acid CoA ligase), and repressed their transcription. Furthermore, we explored the interaction relationships of SACE_3446 and previously identified TFRs (SACE_3986 and SACE_7301) associated with erythromycin production. Given demonstrated relatively independent regulation mode of SACE_3446 and SACE_3986 in erythromycin biosynthesis, we individually and concomitantly inactivated them in an industrial S. erythraea WB. Compared with WB, the WBΔ3446 and WBΔ3446Δ3986 mutants respectively displayed 36% and 65% yield enhancement of erythromycin A, following significantly elevated transcription of eryAI and ermE. When cultured in a 5 L fermentor, erythromycin A of WBΔ3446 and WBΔ3446Δ3986 successively reached 4095 mg/L and 4670 mg/L with 23% and 41% production improvement relative to WB. The strategy reported here will be useful to improve antibiotics production in other industrial actinomycete.
en
Inactivation of SACE_3446, a TetR family transcriptional regulator, stimulates erythromycin production in Saccharopolyspora erythraea.
Article
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oai:repository.helmholtz-hzi.de:10033/6212342019-11-28T09:39:39Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Wang, Hailong
author
Li, Zhen
author
Jia, Ruonan
author
Yin, Jia
author
Li, Aiying
author
Xia, Liqiu
author
Yin, Yulong
author
Müller, Rolf
author
Fu, Jun
author
Stewart, A Francis
author
Zhang, Youming
department
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2018-01-16T10:22:50Z
2017-12-12
ExoCET: exonuclease in vitro assembly combined with RecET recombination for highly efficient direct DNA cloning from complex genomes. 2017 Nucleic Acids Res.
1362-4962
29240926
10.1093/nar/gkx1249
http://hdl.handle.net/10033/621234
Nucleic acids research
The exponentially increasing volumes of DNA sequence data highlight the need for new DNA cloning methods to explore the new information. Here, we describe 'ExoCET' (Exonuclease Combined with RecET recombination) to directly clone any chosen region from bacterial and mammalian genomes with nucleotide precision into operational plasmids. ExoCET combines in vitro exonuclease and annealing with the remarkable capacity of full length RecET homologous recombination (HR) to retrieve specified regions from genomic DNA preparations. Using T4 polymerase (T4pol) as the in vitro exonuclease for ExoCET, we directly cloned large regions (>50 kb) from bacterial and mammalian genomes, including DNA isolated from blood. Employing RecET HR or Cas9 cleavage in vitro, the directly cloned region can be chosen with nucleotide precision to position, for example, a gene into an expression vector without the need for further subcloning. In addition to its utility for bioprospecting in bacterial genomes, ExoCET presents straightforward access to mammalian genomes for various applications such as region-specific DNA sequencing that retains haplotype phasing, the rapid construction of optimal, haplotypic, isogenic targeting constructs or a new way to genotype that presents advantages over Southern blotting or polymerase chain reaction. The direct cloning capacities of ExoCET present new freedoms in recombinant DNA technology.
en
ExoCET: exonuclease in vitro assembly combined with RecET recombination for highly efficient direct DNA cloning from complex genomes.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6212672019-08-30T11:37:24Zcom_10033_620618col_10033_620619
Helmholtz Zentrum für Infektionsforschung Repository
author
Zaburannyi, Nestor
author
Grosser, Katrin
author
Gasparoni, Gilles
author
Müller, Rolf
author
Schrallhammer, Martina
author
Simon, Martin
department
Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2018-02-07T15:38:50Z
2018-01-18
Draft Genome Sequence and Annotation of the Obligate Bacterial Endosymbiont Caedibacter taeniospiralis, Causative Agent of the Killer Phenotype in Paramecium tetraurelia. 2018, 6 (3) Genome Announc
2169-8287
29348333
10.1128/genomeA.01418-17
http://hdl.handle.net/10033/621267
Genome announcements
Caedibacter taeniospiralis is an obligate endosymbiont living in the cytoplasm of Paramecium tetraureliaC. taeniospiralis causes the so-called killer trait, eliminating intraspecific competitors of its host when released into the medium by the concerted action of the unusual protein structure R-body (refractile body) in addition to an as-yet-unknown toxin.
en
Draft Genome Sequence and Annotation of the Obligate Bacterial Endosymbiont Caedibacter taeniospiralis, Causative Agent of the Killer Phenotype in Paramecium tetraurelia.
Article
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