• Acetyl-CoA carboxylase 1 regulates endothelial cell migration by shifting the phospholipid composition.

      Glatzel, Daniel K; Koeberle, Andreas; Pein, Helmut; Löser, Konstantin; Stark, Anna; Keksel, Nelli; Werz, Oliver; Müller, Rolf; Bischoff, Iris; Fürst, Robert; HIPS, Helmholtz-Institute für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany. (2018-02)
      The enzyme acetyl-CoA carboxylase (ACC) plays a crucial role in fatty acid metabolism. In recent years, ACC has been recognized as a promising drug target for treating different diseases. However, the role of ACC in vascular endothelial cells (ECs) has been neglected so far. To characterize the role of ACC, we used the ACC inhibitor, soraphen A, as a chemical tool, and also a gene silencing approach. We found that ACC1 was the predominant isoform in human umbilical vein ECs as well as in human microvascular ECs and that soraphen A reduced the levels of malonyl-CoA. We revealed that ACC inhibition shifted the lipid composition of EC membranes. Accordingly, membrane fluidity, filopodia formation, and migratory capacity were reduced. The antimigratory action of soraphen A depended on an increase in the cellular proportion of PUFAs and, most importantly, on a decreased level of phosphatidylglycerol. Our study provides a causal link between ACC, membrane lipid composition, and cell migration in ECs. Soraphen A represents a useful chemical tool to investigate the role of fatty acid metabolism in ECs and ACC inhibition offers a new and valuable therapeutic perspective for the treatment of EC migration-related diseases.
    • Aethiopinolones A-E, New Pregnenolone Type Steroids from the East African Basidiomycete Fomitiporia aethiopica.

      Chepkirui, Clara; Sum, Winnie C; Cheng, Tian; Matasyoh, Josphat C; Decock, Cony; Stadler, Marc; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-02-09)
      A mycelial culture of the Kenyan basidiomyceteFomitiporia aethiopicawas fermented on rice and the cultures were extracted with methanol. Subsequent HPLC profiling and preparative chromatography of its crude extract led to the isolation of five previously undescribed pregnenolone type triterpenes1-5, for which we propose the trivial name aethiopinolones A-E. The chemical structures of the aethiopinolones were determined by extensive 1D- and 2D-NMR, and HRMS data analysis. The compounds exhibited moderate cytotoxic effects against various human cancer cell lines, but they were found devoid of significant nematicidal and antimicrobial activities.
    • Akanthopyrones A-D, α-Pyrones Bearing a 4-O-Methyl-β-d-glucopyranose Moiety from the Spider-Associated Ascomycete Akanthomyces novoguineensis.

      Kuephadungphan, Wilawan; Helaly, Soleiman E; Daengrot, Charuwan; Phongpaichit, Souwalak; Luangsa-Ard, Janet Jennifer; Rukachaisirikul, Vatcharin; Stadler, Marc; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-07-18)
      Hypocrealean fungi have proved to be prolific bioactive metabolite producers; they have caught the attention of mycologists throughout the world. However, only a few studies on the insect and spider parasitic genus Akanthomyces have so far been carried out. In this study, we report the isolation, structural elucidation and biological activities of four unprecedented glycosylated α-pyrone derivatives, akanthopyrones A-D (1-4), from a culture of Akanthomyces novoguineensis collected in Thailand. The chemical structures of the akanthopyrones were determined by extensive 1D- and 2D-NMR, and HRMS spectroscopic analysis. Their absolute configurations were determined. Akanthopyrone A (1) exhibited weak antimicrobial activity against Bacillus subtilis DSM10 and cytotoxicity against the HeLa cell line KB-3-1, while akanthopyrone D (4) showed weak activity against Candida tenuis MUCL 29892.
    • The application of the name Xylaria hypoxylon, based on Clavaria hypoxylon of Linnaeus.

      Stadler, Marc; Hawksworth, David L; Fournier, Jacques (2014-06)
      Although Xylaria hypoxylon is one of the most familiar fungi of temperate regions, the basionym of the name, Clavaria hypoxylon of Linnaeus, has remained untypified. Here we assess the original five elements included in the 1753 protologue; no candidate specimen was located but two illustrations Linnaeus cited were considered, one a mixture of species and the other fanciful. As the name is sanctioned, following clarifications in the Melbourne Code, elements cited by Fries when the name was sanctioned in 1823 are also candidates for lectotypification. In addition to various illustrations, Fries cites two exsiccatae, and one from his own Scleromycetes Suecicae distributed in 1821 is designated as lectotype for Linnaeus' name here. In view of the complexity of the group as revealed by molecular systematic work, and the poor state of the Fries material, we also designate a sequenced epitype from Sweden. We stress the importance of examining fungi in the complex in the sexual state, as those that are asexual can be difficult to identify conclusively. Figures of the original protologues and the most pertinent illustrations and specimens are provided, along with a detailed description and illustrations based on recent collections.
    • Bacterial type III polyketide synthases: phylogenetic analysis and potential for the production of novel secondary metabolites by heterologous expression in pseudomonads.

      Gross, Frank; Luniak, Nora; Perlova, Olena; Gaitatzis, Nikolaos; Jenke-Kodama, Holger; Gerth, Klaus; Gottschalk, Daniela; Dittmann, Elke; Müller, Rolf (2006-03-01)
      Type III polyketide synthases (PKS) were regarded as typical for plant secondary metabolism before they were found in microorganisms recently. Due to microbial genome sequencing efforts, more and more type III PKS are found, most of which of unknown function. In this manuscript, we report a comprehensive analysis of the phylogeny of bacterial type III PKS and report the expression of a type III PKS from the myxobacterium Sorangium cellulosum in pseudomonads. There is no precedent of a secondary metabolite that might be biosynthetically correlated to a type III PKS from any myxobacterium. Additionally, an inactivation mutant of the S. cellulosum gene shows no physiological difference compared to the wild-type strain which is why these type III PKS are assumed to be "silent" under the laboratory conditions administered. One type III PKS (SoceCHS1) was expressed in different Pseudomonas sp. after the heterologous expression in Escherichia coli failed. Cultures of recombinant Pseudomonas sp. harbouring SoceCHS1 turned red upon incubation and the diffusible pigment formed was identified as 2,5,7-trihydroxy-1,4-naphthoquinone, the autooxidation product of 1,3,6,8-tetrahydroxynaphthalene. The successful heterologous production of a secondary metabolite using a gene not expressed under administered laboratory conditions provides evidence for the usefulness of our approach to activate such secondary metabolite genes for the production of novel metabolites.
    • Bioactive Compounds Produced by Hypoxylon fragiforme against Staphylococcus aureus Biofilms.

      Yuyama, Kamila Tomoko; Chepkirui, Clara; Wendt, Lucile; Fortkamp, Diana; Stadler, Marc; Abraham, Wolf-Rainer; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-12-12)
      Treating infections organized in biofilms is a challenge due to the resistance of the pathogens against antibiotics and host immune cells. Many fungi grow in a wet environment, favorable for the growth of bacterial biofilms, and we speculated that fungi possess some strategies to control these bacterial biofilms. A fungus identified as Hypoxylon fragiforme, was collected in the Harz Mountains, Germany, and its mycelial culture was fermented in different culture media for 67 days to test its biological potential against bacterial biofilms. Sclerin, sclerin diacid and its 3-methyl monoester (methyl 1-(5-hydroxy-6-carboxylic-2,3,4-trimethylphenyl) propionate) are here described for the first time from this fungus. Sclerin and its diacid interfered with the biofilm formation of the pathogen Staphylococcus aureus, inhibiting 86% and 80% of the biofilm at 256 μg mL-1, respectively, but not killing the bacterium. Interestingly, the monomethylester of sclerin diacid was inactive. Although these compounds did not possess any activity against a pre-formed biofilm, they prevented its formation at subtoxic concentrations. Furthermore, sclerin and its diacid displayed a high specificity against Staphylococcus aureus, indicating a good strategy against pathogenic biofilms when combined with antibiotics.
    • Botryane, noreudesmane and abietane terpenoids from the ascomycete Hypoxylon rickii.

      Kuhnert, Eric; Surup, Frank; Wiebach, Vincent; Bernecker, Steffen; Stadler, Marc; Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. (2015-09)
      In the course of our screening for new bioactive natural products, a culture of Hypoxylon rickii, a xylariaceous ascomycete collected from the Caribbean island Martinique, was identified as extraordinary prolific producer of secondary metabolites. Ten metabolites of terpenoid origin were isolated from submerged cultures of this species by preparative HPLC. Their structures were elucidated using spectral techniques including 2D NMR and HRESIMS. Three of the compounds were elucidated as new botryanes (1-3) along with three known ones, i.e. (3aS)-3a,5,5,8-tetramethyl-3,3a,4,5-tetrahydro-1H-cyclopenta[de]isochromen-1-one (4), (3aS,8R)-3a,5,5,8-tetramethyl-3,3a,4,5,7,8-hexahydro-1H-cyclopenta[de]isochromen-1-one (5) and botryenanol (6). Further three new sesquiterpenoids featured a 14-noreudesmane-type skeleton and were named hypoxylan A-C (7-9); the diterpenoid rickitin A (10) contains an abietane-type backbone. Compounds 1, 2, 3, 7, and 10 showed cytotoxic effects against murine cells.
    • Carolacton - A macrolide ketocarbonic acid that reduces biofilm formation by the caries- and endocarditis-associated bacterium Streptococcus mutans

      Jansen, Rolf; Microbial Drugs, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig (Germany) (Wiley Interscience, 2010-03)
    • Characterizing the Epothilone Binding Site on β-Tubulin by Photoaffinity Labeling: Identification of β-Tubulin Peptides TARGSQQY and TSRGSQQY as Targets of an Epothilone Photoprobe for Polymerized Tubulin.

      Ranade, Adwait R; Higgins, LeeAnn; Markowski, Todd W; Glaser, Nicole; Kashin, Dmitry; Bai, Ruoli; Hong, Kwon Ho; Hamel, Ernest; Höfle, Gerhard; Georg, Gunda I; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016-04-14)
      Photoaffinity labeling with an epothilone A photoprobe led to the identification of the β-tubulin peptides TARGSQQY and TSRGSQQY as targets of the photoprobe for polymerized tubulin. These peptides represent residues 274-281 in different β-tubulin isotypes. Placing the carbene producing 21-diazo/triazolo moiety of the photoprobe in the vicinity of the TARGSQQY peptide in a homology model of TBB3 predicted a binding pose and conformation of the photoprobe that are very similar to the ones reported for 1) the high resolution cocrystal structure of epothilone A with an α,β-tubulin complex and for 2) a saturation transfer difference NMR and transferred NOESY NMR study of dimeric and polymerized tubulin. Our findings thus provide additional support for these models as physiologically the most relevant among several modes of binding that have been proposed for epothilone A in the taxane pocket of β-tubulin.
    • Chlorotonil A, a macrolide with a unique gem-dichloro-1,3-dione functionality from Sorangium cellulosum, So ce1525.

      Gerth, Klaus; Steinmetz, Heinrich; Höfle, Gerhard; Jansen, Rolf; Helmholtz-Zentrum für Infektionsforschung, Inhoffenstrasse 7, 38124 Braunschweig, Germany. (2008)
    • Cyclic depsipeptides, ichthyopeptins A and B, from Microcystis ichthyoblabe.

      Zainuddin, Elmi N; Mentel, Renate; Wray, Victor; Jansen, Rolf; Nimtz, Manfred; Lalk, Michael; Mundt, Sabine; Institute of Pharmacy, Friedrich-Ludwig-Jahnstrasse 17, Ernst-Moritz-Arndt University, D-17487 Greifswald, Germany. (2007-07)
      Bioassay-guided isolation of antiviral compounds from the cultured cyanobacterium Microcystis ichthyoblabe provided two novel cyclic depsipeptides, ichthyopeptins A (1) and B (2). Their structures were determined by 1D (1H and 13C) and 2D (COSY, TOCSY, ROESY, HMQC, and HMBC) NMR spectra, ESIMS-MS, and amino acid analysis. The fraction containing both cyclic depsipeptides exhibited antiviral activity against influenza A virus with an IC50 value of 12.5 microg/mL.
    • Design, synthesis and biological evaluation of simplified side chains of the macrolide antibiotic etnangien.

      Altendorfer, Mario; Irschik, Herbert; Menche, Dirk; Organische Chemie, Ruprecht-Karls-Universität Heidelberg, INF 270, D-69120 Heidelberg, Germany. (2012-09-01)
      Novel simplified side chains of the potent RNA polymerase inhibitor etnangien were designed, synthesized and evaluated for antibacterial activity against Gram-positive bacteria and one Gram-negative bacterium.
    • Development of an enzyme linked immunosorbent assay for detection of cyathane diterpenoids.

      Shen, Tian; Hof, Lena M; Hausmann, Heike; Stadler, Marc; Zorn, Holger; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2014-11-18)
      So-called cyathane type diterpenoids are produced as secondary metabolites by basidiomycetes. Based on their antibacterial, fungicidal, and cytotoxic properties, cyathane type terpenoids represent interesting target compounds in fungal biotechnology.
    • Discovery and development of the epothilones : a novel class of antineoplastic drugs.

      Reichenbach, Hans; Höfle, Gerhard; Helmholtz-Zentrum für Infektionsforschung, Braunschweig, Germany. hans.reichenbach@helmholtz-hzi.de (2008)
      The epothilones are a novel class of antineoplastic agents possessing antitubulin activity. The compounds were originally identified as secondary metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. Two major compounds, epothilone A and epothilone B, were purified from the S. cellulosum strain So ce90 and their structures were identified as 16-member macrolides. Initial screening with these compounds revealed a very narrow and selective antifungal activity against the zygomycete, Mucor hiemalis. In addition, strong cytotoxic activity against eukaryotic cells, mouse L929 fibroblasts and human T-24 bladder carcinoma cells was observed. Subsequent studies revealed that epothilones induce tubulin polymerization and enhance microtubule stability. Epothilone-induced stabilisation of microtubules was shown to cause arrest at the G2/M transition of the cell cycle and apoptosis. The compounds are active against cancer cells that have developed resistance to taxanes as a result of acquisition of beta-tubulin overexpression or mutations and against multidrug-resistant cells that overexpress P-glycoprotein or multidrug resistance-associated protein. Thus, epothilones represent a new class of antimicrotubule agents with low susceptibility to key tumour resistance mechanisms.More recently, a range of synthetic and semisynthetic epothilone analogues have been produced to further improve the adverse effect profile (or therapeutic window) and to maximize pharmacokinetic and antitumour properties. Various epothilone analogues have demonstrated activity against many tumour types in preclinical studies and several compounds have been and still are being evaluated in clinical trials. This article reviews the identification and early molecular characterization of the epothilones, which has provided insight into the mode of action of these novel antitumour agents in vivo.
    • Edonamides, the first secondary metabolites from the recently described myxobacterium Aggregicoccus edonensis

      Karwehl, Sabrina; Mohr, Kathrin I.; Jansen, Rolf; Sood, Sakshi; Bernecker, Steffen; Stadler, Marc; Helmholtz Centre for Infection Research,Inhoffenstr. 7; 38124 Braunschweig, Germany. (2015-11)
    • Elsinopirins A-D, Decalin Polyketides from the Ascomycete Elsinoё pyri.

      Surup, Frank; Pommerehne, Kathrin; Schroers, Hans-Josef; Stadler, Marc; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-02-05)
      In course of our screening for new secondary metabolites from ecological niche specialized, phytopathogenic fungi, the plant pathogenElsinoё pyri, strain 2203C, was found to produce four novel compounds (1-4), which were named elsinopirins A-D, in addition to the known metabolite elsinochrome A (5). After isolation by preparative high-performance liquid chromatography (HPLC), their structures, including relative stereochemistry, were elucidated by 1D and 2D nuclear magnetic resonance (NMR) and mass spectrometry (MS) data. Finally, absolute stereochemistry was assigned by chemical shifts of Mosher's esters (α-methoxy-α-trifluoromethylphenylacetic acid; MTPA) derivatives of elsinopirin B (2). The compounds were found to be devoid of significant antibacterial, antifungal, and cytotoxic activities.
    • Evolution of Xylariomycetidae (Ascomycota: Sordariomycetes)

      Samarakoon, MC et al.; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016)
    • Five Unprecedented Secondary Metabolites from the Spider Parasitic Fungus Akanthomyces novoguineensis.

      Helaly, Soleiman E; Kuephadungphan, Wilawan; Phongpaichit, Souwalak; Luangsa-Ard, Janet Jennifer; Rukachaisirikul, Vatcharin; Stadler, Marc; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-06-14)
      Five new compounds including the glycosylated β-naphthol (1, akanthol), a glycosylated pyrazine (2, akanthozine), and three amide derivatives including a hydroxamic acid derivative (3-5) were isolated from the spider-associated fungus Akanthomyces novoguineensis (Cordycipitaceae, Ascomycota). Their structures were elucidated by using high resolution mass spectrometry (HRMS) and NMR spectroscopy. In this study, the antimicrobial, cytotoxic, anti-biofilm, and nematicidal activities of the new compounds were evaluated. The distribution pattern of secondary metabolites in the species was also revealed in which more isolates of A. novoguineensis were encountered and their secondary metabolite profiles were examined using analytical HPLC with diode array and mass spectrometric detection (HPLC-DAD/MS). Remarkably, all isolated compounds are specifically produced by A. novoguineensis.
    • Fungal natural products-the mushroom perspective.

      Stadler, Marc; Hoffmeister, Dirk; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2015)
    • Furanones and Anthranilic Acid Derivatives from the Endophytic Fungus Dendrothyrium variisporum.

      Teponno, Rémy B; Noumeur, Sara R; Helaly, Soleiman E; Hüttel, Stephan; Harzallah, Daoud; Stadler, Marc; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-10-09)
      Extracts from an endophytic fungus isolated from the roots of the Algerian plant Globularia alypum showed prominent antimicrobial activity in a screening for novel antibiotics. The producer organism was identified as Dendrothyrium variisporum by means of morphological studies and molecular phylogenetic methods. Studies on the secondary metabolite production of this strain in various culture media revealed that the major components from shake flasks were massarilactones D (1) and H (2) as well as two new furanone derivatives for which we propose the trivial names (5S)-cis-gregatin B (3) and graminin D (4). Scale-up of the fermentation in a 10 L bioreactor yielded massarilactone D and several further metabolites. Among those were three new anthranilic acid derivatives (5-7), two known anthranilic acid analogues (8 and 9) and three cyclopeptides (10-12). Their structures were elucidated on the basis of extensive spectroscopic analysis (1D- and 2D-NMR), high-resolution mass spectrometry (HRESIMS), and the application of the modified Mosher's method. The isolated metabolites were tested for antimicrobial and cytotoxic activities against various bacteria, fungi, and two mammalian cell lines. The new Metabolite 5 and Compound 9 exhibited antimicrobial activity while Compound 9 showed cytotoxicity activity against KB3.1 cells.