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Wohlschlager, Therese
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Sutov, Grigorij
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Gauss, Robert
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Hauck, Dirk
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Schmieder, Stefanie S
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Knobel, Martin
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Titz, Alexander
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Dell, Anne
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Haslam, Stuart M
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Hengartner, Michael O
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Aebi, Markus
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Künzler, Markus
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2014-09-12T09:43:18Z
2014-09-12T09:43:18Z
2014-07-08
Methylated glycans as conserved targets of animal and fungal innate defense. 2014, 111 (27):E2787-96 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
24879441
10.1073/pnas.1401176111
http://hdl.handle.net/10033/326069
Proceedings of the National Academy of Sciences of the United States of America
Effector proteins of innate immune systems recognize specific non-self epitopes. Tectonins are a family of β-propeller lectins conserved from bacteria to mammals that have been shown to bind bacterial lipopolysaccharide (LPS). We present experimental evidence that two Tectonins of fungal and animal origin have a specificity for O-methylated glycans. We show that Tectonin 2 of the mushroom Laccaria bicolor (Lb-Tec2) agglutinates Gram-negative bacteria and exerts toxicity toward the model nematode Caenorhabditis elegans, suggesting a role in fungal defense against bacteria and nematodes. Biochemical and genetic analysis of these interactions revealed that both bacterial agglutination and nematotoxicity of Lb-Tec2 depend on the recognition of methylated glycans, namely O-methylated mannose and fucose residues, as part of bacterial LPS and nematode cell-surface glycans. In addition, a C. elegans gene, termed samt-1, coding for a candidate membrane transport protein for the presumptive donor substrate of glycan methylation, S-adenosyl-methionine, from the cytoplasm to the Golgi was identified. Intriguingly, limulus lectin L6, a structurally related antibacterial protein of the Japanese horseshoe crab Tachypleus tridentatus, showed properties identical to the mushroom lectin. These results suggest that O-methylated glycans constitute a conserved target of the fungal and animal innate immune system. The broad phylogenetic distribution of O-methylated glycans increases the spectrum of potential antagonists recognized by Tectonins, rendering this conserved protein family a universal defense armor.
en
Archived with thanks to Proceedings of the National Academy of Sciences of the United States of America
Methylated glycans as conserved targets of animal and fungal innate defense.
Article
2018-06-13T04:02:01Z
Effector proteins of innate immune systems recognize specific non-self epitopes. Tectonins are a family of β-propeller lectins conserved from bacteria to mammals that have been shown to bind bacterial lipopolysaccharide (LPS). We present experimental evidence that two Tectonins of fungal and animal origin have a specificity for O-methylated glycans. We show that Tectonin 2 of the mushroom Laccaria bicolor (Lb-Tec2) agglutinates Gram-negative bacteria and exerts toxicity toward the model nematode Caenorhabditis elegans, suggesting a role in fungal defense against bacteria and nematodes. Biochemical and genetic analysis of these interactions revealed that both bacterial agglutination and nematotoxicity of Lb-Tec2 depend on the recognition of methylated glycans, namely O-methylated mannose and fucose residues, as part of bacterial LPS and nematode cell-surface glycans. In addition, a C. elegans gene, termed samt-1, coding for a candidate membrane transport protein for the presumptive donor substrate of glycan methylation, S-adenosyl-methionine, from the cytoplasm to the Golgi was identified. Intriguingly, limulus lectin L6, a structurally related antibacterial protein of the Japanese horseshoe crab Tachypleus tridentatus, showed properties identical to the mushroom lectin. These results suggest that O-methylated glycans constitute a conserved target of the fungal and animal innate immune system. The broad phylogenetic distribution of O-methylated glycans increases the spectrum of potential antagonists recognized by Tectonins, rendering this conserved protein family a universal defense armor.
ORIGINAL
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Helmholtz Zentrum für Infektionsforschung Repository
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oai:repository.helmholtz-hzi.de:10033/3365532019-08-30T11:36:05Zcom_10033_620656col_10033_620658
Butschi, Alex
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Titz, Alexander
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Wälti, Martin A
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Olieric, Vincent
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Paschinger, Katharina
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Nöbauer, Katharina
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Guo, Xiaoqiang
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Seeberger, Peter H
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Wilson, Iain B H
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Aebi, Markus
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Hengartner, Michael O
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Institute of Molecular Biology, University of Zürich, Zürich, Switzerland.
2014-12-03T10:32:51Z
2014-12-03T10:32:51Z
2010-01
Caenorhabditis elegans N-glycan core beta-galactoside confers sensitivity towards nematotoxic fungal galectin CGL2. 2010, 6 (1):e1000717 PLoS Pathog.
1553-7374
20062796
10.1371/journal.ppat.1000717
http://hdl.handle.net/10033/336553
PLoS pathogens
The physiological role of fungal galectins has remained elusive. Here, we show that feeding of a mushroom galectin, Coprinopsis cinerea CGL2, to Caenorhabditis elegans inhibited development and reproduction and ultimately resulted in killing of this nematode. The lack of toxicity of a carbohydrate-binding defective CGL2 variant and the resistance of a C. elegans mutant defective in GDP-fucose biosynthesis suggested that CGL2-mediated nematotoxicity depends on the interaction between the galectin and a fucose-containing glycoconjugate. A screen for CGL2-resistant worm mutants identified this glycoconjugate as a Galbeta1,4Fucalpha1,6 modification of C. elegans N-glycan cores. Analysis of N-glycan structures in wild type and CGL2-resistant nematodes confirmed this finding and allowed the identification of a novel putative glycosyltransferase required for the biosynthesis of this glycoepitope. The X-ray crystal structure of a complex between CGL2 and the Galbeta1,4Fucalpha1,6GlcNAc trisaccharide at 1.5 A resolution revealed the biophysical basis for this interaction. Our results suggest that fungal galectins play a role in the defense of fungi against predators by binding to specific glycoconjugates of these organisms.
en
Agaricales
Amino Acid Sequence
Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Fungal Proteins
Galactosides
Galectin 2
Molecular Sequence Data
Nematode Infections
Protein Structure, Quaternary
Structure-Activity Relationship
Caenorhabditis elegans N-glycan core beta-galactoside confers sensitivity towards nematotoxic fungal galectin CGL2.
Article
2018-06-13T03:47:23Z
The physiological role of fungal galectins has remained elusive. Here, we show that feeding of a mushroom galectin, Coprinopsis cinerea CGL2, to Caenorhabditis elegans inhibited development and reproduction and ultimately resulted in killing of this nematode. The lack of toxicity of a carbohydrate-binding defective CGL2 variant and the resistance of a C. elegans mutant defective in GDP-fucose biosynthesis suggested that CGL2-mediated nematotoxicity depends on the interaction between the galectin and a fucose-containing glycoconjugate. A screen for CGL2-resistant worm mutants identified this glycoconjugate as a Galbeta1,4Fucalpha1,6 modification of C. elegans N-glycan cores. Analysis of N-glycan structures in wild type and CGL2-resistant nematodes confirmed this finding and allowed the identification of a novel putative glycosyltransferase required for the biosynthesis of this glycoepitope. The X-ray crystal structure of a complex between CGL2 and the Galbeta1,4Fucalpha1,6GlcNAc trisaccharide at 1.5 A resolution revealed the biophysical basis for this interaction. Our results suggest that fungal galectins play a role in the defense of fungi against predators by binding to specific glycoconjugates of these organisms.
ORIGINAL
Butschi et al_final.pdf
Butschi et al_final.pdf
Open Access publication
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/3365872019-08-30T11:36:32Zcom_10033_620656col_10033_620658
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Exner, Thomas E
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Titz, Alexander
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Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C 2.3, D-66123, Saarbrücken, Germany; Department of Chemistry and Graduate School Chemical Biology, University of Konstanz, D-78457, Konstanz, Germany.
2014-12-04T10:46:13Z
2014-12-04T10:46:13Z
2014
A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB. 2014, 9 (11):e112822 PLoS ONE
1932-6203
25415418
10.1371/journal.pone.0112822
http://hdl.handle.net/10033/336587
PloS one
The rise of resistances against antibiotics in bacteria is a major threat for public health and demands the development of novel antibacterial therapies. Infections with Pseudomonas aeruginosa are a severe problem for hospitalized patients and for patients suffering from cystic fibrosis. These bacteria can form biofilms and thereby increase their resistance towards antibiotics. The bacterial lectin LecB was shown to be necessary for biofilm formation and the inhibition with its carbohydrate ligands resulted in reduced amounts of biofilm. The natural ligands for LecB are glycosides of d-mannose and l-fucose, the latter displaying an unusual strong affinity. Interestingly, although mannosides are much weaker ligands for LecB, they do form an additional hydrogen bond with the protein in the crystal structure. To analyze the individual contributions of the methyl group in fucosides and the hydroxymethyl group in mannosides to the binding, we designed and synthesized derivatives of these saccharides. We report glycomimetic inhibitors that dissect the individual interactions of their saccharide precursors with LecB and give insight into the biophysics of binding by LecB. Furthermore, theoretical calculations supported by experimental thermodynamic data suggest a perturbed hydrogen bonding network for mannose derivatives as molecular basis for the selectivity of LecB for fucosides. Knowledge gained on the mode of interaction of LecB with its ligands at ambient conditions will be useful for future drug design.
en
A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB.
Article
2018-06-13T20:04:59Z
The rise of resistances against antibiotics in bacteria is a major threat for public health and demands the development of novel antibacterial therapies. Infections with Pseudomonas aeruginosa are a severe problem for hospitalized patients and for patients suffering from cystic fibrosis. These bacteria can form biofilms and thereby increase their resistance towards antibiotics. The bacterial lectin LecB was shown to be necessary for biofilm formation and the inhibition with its carbohydrate ligands resulted in reduced amounts of biofilm. The natural ligands for LecB are glycosides of d-mannose and l-fucose, the latter displaying an unusual strong affinity. Interestingly, although mannosides are much weaker ligands for LecB, they do form an additional hydrogen bond with the protein in the crystal structure. To analyze the individual contributions of the methyl group in fucosides and the hydroxymethyl group in mannosides to the binding, we designed and synthesized derivatives of these saccharides. We report glycomimetic inhibitors that dissect the individual interactions of their saccharide precursors with LecB and give insight into the biophysics of binding by LecB. Furthermore, theoretical calculations supported by experimental thermodynamic data suggest a perturbed hydrogen bonding network for mannose derivatives as molecular basis for the selectivity of LecB for fucosides. Knowledge gained on the mode of interaction of LecB with its ligands at ambient conditions will be useful for future drug design.
ORIGINAL
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oai:repository.helmholtz-hzi.de:10033/3367002019-08-30T11:36:32Zcom_10033_620656col_10033_620658
Sommer, Roman
ab94b5af1a59bace7c8bfbc08f572b29
500
Joachim, Ines
e3e184873e8376884d46e8a942d2d271
500
Wagner, Stefanie
935803ea3ccfe8267a16e098ea9a33bc
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Titz, Alexander
bbe73a0250cae3389056476be5d00d1b
500
University of Konstanz, Department of Chemistry and Zukunftskolleg, Universitätsstrasse 10, D-78457 Konstanz.
2014-12-05T09:59:07Z
2014-12-05T09:59:07Z
2013
New approaches to control infections: anti-biofilm strategies against gram-negative bacteria. 2013, 67 (4):286-90 Chimia (Aarau)
0009-4293
23967708
http://hdl.handle.net/10033/336700
Chimia
Hospital-acquired bacterial infections, especially with Gram-negative pathogens, present a major threat due to the rapid spread of antibiotic-resistant strains. Targeting mechanisms of bacterial virulence has recently appeared as a promising new therapeutic paradigm. Biofilm formation is a bacterial lifestyle, which offers a survival advantage through its protective matrix against host immune defense and antibiotic treatment. Interfering with biogenesis of adhesive organelles, bacterial communication or carbohydrate-mediated adhesion as anti-biofilm strategies are reviewed.
en
Anti-Bacterial Agents
Biofilms
Cross Infection
Gram-Negative Bacteria
Gram-Negative Bacterial Infections
Humans
New approaches to control infections: anti-biofilm strategies against gram-negative bacteria.
Article
2018-06-13T21:23:47Z
Hospital-acquired bacterial infections, especially with Gram-negative pathogens, present a major threat due to the rapid spread of antibiotic-resistant strains. Targeting mechanisms of bacterial virulence has recently appeared as a promising new therapeutic paradigm. Biofilm formation is a bacterial lifestyle, which offers a survival advantage through its protective matrix against host immune defense and antibiotic treatment. Interfering with biogenesis of adhesive organelles, bacterial communication or carbohydrate-mediated adhesion as anti-biofilm strategies are reviewed.
ORIGINAL
Sommer et al_2013final.pdf
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oai:repository.helmholtz-hzi.de:10033/3366982019-08-30T11:27:43Zcom_10033_620656col_10033_620658
Titz, Alexander
bbe73a0250cae3389056476be5d00d1b
500
Ernst, Beat
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500
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C 2.3, D-66123, Saarbrücken, Germany
2014-12-05T09:45:07Z
2014-12-05T09:45:07Z
2014-12-05
Mimetics of Sialyl Lewis<SUP>x</SUP>: The Pre-Organization of the Carboxylic Acid is Essential for Binding to Selectins 2007, 61 (4):194 CHIMIA International Journal for Chemistry
00094293
00000000
10.2533/chimia.2007.194
http://hdl.handle.net/10033/336698
CHIMIA International Journal for Chemistry
http://openurl.ingenta.com/content/xref?genre=article&issn=0009-4293&volume=61&issue=4&spage=194
Mimetics of Sialyl Lewis<SUP>x</SUP>: The Pre-Organization of the Carboxylic Acid is Essential for Binding to Selectins
Meetings and Proceedings
2018-06-12T17:47:00Z
ORIGINAL
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Titz, Alexander
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hemical Biology of Carbohydrates, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), D-66123 Saarbrücken, Germany.
2015-06-11T14:17:27Z
2015-06-11T14:17:27Z
2015-05-05
Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa. 2015, 412:34-42 Carbohydr. Res.
1873-426X
26004349
10.1016/j.carres.2015.04.010
http://hdl.handle.net/10033/556781
Carbohydrate research
Biofilm formation and chronic infections with Pseudomonas aeruginosa depend on lectins produced by the bacterium. The bacterial C-type lectin LecB binds to the two monosaccharides l-fucose and d-mannose and conjugates thereof. Previously, d-mannose derivatives with amide and sulfonamide substituents at C6 were reported as potent inhibitors of the bacterial lectin LecB and LecB-mediated bacterial surface adhesion. Because d-mannose establishes a hydrogen bond via its 6-OH group with Ser23 of LecB in the crystal structure and may be beneficial for binding affinity, we extended d-mannose and synthesized mannoheptoses bearing the free 6-OH group as well as amido and sulfonamido-substituents at C7. Two series of diastereomeric mannoheptoses were synthesized and the stereochemistry was determined by X-ray crystallography. The potency of the mannoheptoses as LecB inhibitors was assessed in a competitive binding assay. The data reveal a diastereoselectivity of LecB for (6S)-mannoheptose derivatives with increased activity over methyl α-d-mannoside.
ENG
Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa.
Article
2016-08-15T00:00:00Z
Biofilm formation and chronic infections with Pseudomonas aeruginosa depend on lectins produced by the bacterium. The bacterial C-type lectin LecB binds to the two monosaccharides l-fucose and d-mannose and conjugates thereof. Previously, d-mannose derivatives with amide and sulfonamide substituents at C6 were reported as potent inhibitors of the bacterial lectin LecB and LecB-mediated bacterial surface adhesion. Because d-mannose establishes a hydrogen bond via its 6-OH group with Ser23 of LecB in the crystal structure and may be beneficial for binding affinity, we extended d-mannose and synthesized mannoheptoses bearing the free 6-OH group as well as amido and sulfonamido-substituents at C7. Two series of diastereomeric mannoheptoses were synthesized and the stereochemistry was determined by X-ray crystallography. The potency of the mannoheptoses as LecB inhibitors was assessed in a competitive binding assay. The data reveal a diastereoselectivity of LecB for (6S)-mannoheptose derivatives with increased activity over methyl α-d-mannoside.
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Helmholtz Zentrum für Infektionsforschung Repository
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Helmholtz Institute for Pharmaceutical Research Saarland (HIPS);Saarland University, Building A4.1, 66123 Saarbruecken, Germany.
Chemical Biology of Carbohydrates; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); Universitätsstrasse 10 66123 Saarbrücken Germany
Chemical Biology of Carbohydrates; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); Universitätsstrasse 10 66123 Saarbrücken Germany
Centre de Recherche sur les Macromolécules Végétales (CERMAV-UPR5301); CNRS and Université Grenoble Alpes, BP53; 38041 Grenoble cedex 9 France
Chemical Biology of Carbohydrates; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); Universitätsstrasse 10 66123 Saarbrücken Germany
Centre de Recherche sur les Macromolécules Végétales (CERMAV-UPR5301); CNRS and Université Grenoble Alpes, BP53; 38041 Grenoble cedex 9 France
Department of Chemistry and Graduate School Chemical Biology; University of Konstanz; 78457 Konstanz Germany
Department of Chemistry and Graduate School Chemical Biology; University of Konstanz; 78457 Konstanz Germany
Centre de Recherche sur les Macromolécules Végétales (CERMAV-UPR5301); CNRS and Université Grenoble Alpes, BP53; 38041 Grenoble cedex 9 France
Chemical Biology of Carbohydrates; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); Universitätsstrasse 10 66123 Saarbrücken Germany
2016-01-19T14:44:13Z
2016-01-19T14:44:13Z
2015-12
Cinnamide Derivatives of d -Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa 2015, 4 (6):756 ChemistryOpen
21911363
10.1002/open.201500162
http://hdl.handle.net/10033/594053
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http://doi.wiley.com/10.1002/open.201500162
Cinnamide Derivatives of d -Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa
Article
2018-06-13T04:24:26Z
ORIGINAL
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6112232019-08-30T11:33:29Zcom_10033_620656col_10033_620658
Sommer, Roman
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500
Wagner, Stefanie
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500
Varrot, Annabelle
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500
Nycholat, Corwin M.
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Khaledi, Ariane
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Häussler, Susanne
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http://orcid.org/0000-0001-6141-9102
Paulson, James C.
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500
Imberty, Anne
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500
Titz, Alexander
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600
http://orcid.org/0000-0001-7408-5084
2016-05-31T08:39:04Z
2016-05-31T08:39:04Z
2016
The virulence factor LecB varies in clinical isolates: consequences for ligand binding and drug discovery 2016 Chem. Sci.
2041-6520
2041-6539
10.1039/C6SC00696E
http://hdl.handle.net/10033/611223
Chem. Sci.
http://xlink.rsc.org/?DOI=C6SC00696E
The virulence factor LecB varies in clinical isolates: consequences for ligand binding and drug discovery
Article
2018-06-12T16:46:00Z
ORIGINAL
Sommer et al.pdf
Sommer et al.pdf
Open Access publication
application/pdf
2649803
https://hzi.openrepository.com/bitstream/10033/611223/1/Sommer%20et%20al.pdf
df17d7a4dae4d010b6f89bc86f7587a0
MD5
1
true
Sommer_supp.pdf
Sommer_supp.pdf
supplemental material
application/pdf
2277328
https://hzi.openrepository.com/bitstream/10033/611223/2/Sommer_supp.pdf
543d008dfe16e5e7f998f3ee9d624060
MD5
2
false
CC-LICENSE
license_url
license_url
text/plain
49
https://hzi.openrepository.com/bitstream/10033/611223/3/license_url
924993ce0b3ba389f79f32a1b2735415
MD5
3
false
license_text
license_text
application/octet-stream
22333
https://hzi.openrepository.com/bitstream/10033/611223/4/license_text
33af6f23fea3b848a02227818b46d2ee
MD5
4
false
license_rdf
license_rdf
application/octet-stream
23748
https://hzi.openrepository.com/bitstream/10033/611223/5/license_rdf
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MD5
5
false
LICENSE
license.txt
license.txt
text/plain
1685
https://hzi.openrepository.com/bitstream/10033/611223/6/license.txt
cb598eeb10bfed09d26fd8d285172ad4
MD5
6
false
THUMBNAIL
Sommer et al.pdf.jpg
Sommer et al.pdf.jpg
Generated Thumbnail
image/jpeg
106223
https://hzi.openrepository.com/bitstream/10033/611223/13/Sommer%20et%20al.pdf.jpg
0bf0055950a66af84bf28cfbcc7e9d8c
MD5
13
false
Sommer_supp.pdf.jpg
Sommer_supp.pdf.jpg
Generated Thumbnail
image/jpeg
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https://hzi.openrepository.com/bitstream/10033/611223/14/Sommer_supp.pdf.jpg
67c6f94eb5af56c129c40eb09f55bc8f
MD5
14
false
TEXT
Sommer_supp.pdf.txt
Sommer_supp.pdf.txt
Extracted Text
text/plain
36344
https://hzi.openrepository.com/bitstream/10033/611223/8/Sommer_supp.pdf.txt
d414db75fb211da96d0e9e146f15c805
MD5
8
false
Sommer et al.pdf.txt
Sommer et al.pdf.txt
Extracted Text
text/plain
47172
https://hzi.openrepository.com/bitstream/10033/611223/10/Sommer%20et%20al.pdf.txt
92a2d6b22e844fb3977cca3f3268e5a9
MD5
10
false
10033/611223
oai:hzi.openrepository.com:10033/611223
2019-08-30 11:33:29.68
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6112592019-08-30T11:33:25Zcom_10033_620656col_10033_620658
Beshr, Ghamdan
bd56df65fbfa89ea13c42f39acb82f8f
500
Sommer, Roman
ab94b5af1a59bace7c8bfbc08f572b29
500
Hauck, Dirk
d78a0493e67fa8730a16d78132dc6953
500
Siebert, David Chan Bodin
f38dddeefd38b60cf54348929fc0284b
500
Hofmann, Anna
2d98082aad6b27b0e2462ce70825eb6b
500
Imberty, Anne
6e3e5ebf482abdb8033b0c4c8cfa10db
500
Titz, Alexander
bbe73a0250cae3389056476be5d00d1b
500
2016-05-31T14:35:19Z
2016-05-31T14:35:19Z
2016
Development of a competitive binding assay for the Burkholderia cenocepacia lectin BC2L-A and structure activity relationship of natural and synthetic inhibitors 2016, 7 (3):519 Med. Chem. Commun.
2040-2503
2040-2511
10.1039/C5MD00557D
http://hdl.handle.net/10033/611259
Med. Chem. Commun.
http://xlink.rsc.org/?DOI=C5MD00557D
Development of a competitive binding assay for the Burkholderia cenocepacia lectin BC2L-A and structure activity relationship of natural and synthetic inhibitors
Article
2017-01-15T00:00:00Z
ORIGINAL
Beshr et al.pdf
Beshr et al.pdf
original manuscript
application/pdf
1442713
https://hzi.openrepository.com/bitstream/10033/611259/1/Beshr%20et%20al.pdf
fa88b3fc9cb9475a59f5b382a2e2fd34
MD5
1
true
S_info.pdf
S_info.pdf
supporting information
application/pdf
1945792
https://hzi.openrepository.com/bitstream/10033/611259/2/S_info.pdf
ca13f62da52e90d012ab6ed94126784c
MD5
2
false
CC-LICENSE
license_url
license_url
text/plain
49
https://hzi.openrepository.com/bitstream/10033/611259/3/license_url
924993ce0b3ba389f79f32a1b2735415
MD5
3
false
license_text
license_text
application/octet-stream
22333
https://hzi.openrepository.com/bitstream/10033/611259/4/license_text
33af6f23fea3b848a02227818b46d2ee
MD5
4
false
license_rdf
license_rdf
application/octet-stream
23748
https://hzi.openrepository.com/bitstream/10033/611259/5/license_rdf
b92763cfc0af52c7c868455edfaf3266
MD5
5
false
LICENSE
license.txt
license.txt
text/plain
1685
https://hzi.openrepository.com/bitstream/10033/611259/6/license.txt
cb598eeb10bfed09d26fd8d285172ad4
MD5
6
false
TEXT
Beshr et al.pdf.txt
Beshr et al.pdf.txt
Extracted Text
text/plain
54907
https://hzi.openrepository.com/bitstream/10033/611259/7/Beshr%20et%20al.pdf.txt
7b9c8bf039879651492246d0fbf0b29c
MD5
7
false
S_info.pdf.txt
S_info.pdf.txt
Extracted Text
text/plain
2615
https://hzi.openrepository.com/bitstream/10033/611259/9/S_info.pdf.txt
9a601e0bf325bfc7f46c9c2212105632
MD5
9
false
THUMBNAIL
Beshr et al.pdf.jpg
Beshr et al.pdf.jpg
Generated Thumbnail
image/jpeg
43006
https://hzi.openrepository.com/bitstream/10033/611259/11/Beshr%20et%20al.pdf.jpg
638d5b3cf1a4369ec06ed9a84b88737b
MD5
11
false
S_info.pdf.jpg
S_info.pdf.jpg
Generated Thumbnail
image/jpeg
44240
https://hzi.openrepository.com/bitstream/10033/611259/12/S_info.pdf.jpg
e4732df96848f4f77ab3ab7bbddbe657
MD5
12
false
10033/611259
oai:hzi.openrepository.com:10033/611259
2019-08-30 11:33:25.329
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6208052019-08-30T11:36:32Zcom_10033_620656col_10033_620658
Sommer, Roman
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500
Hauck, Dirk
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500
Varrot, Annabelle
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500
Imberty, Anne
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500
Künzler, Markus
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500
Titz, Alexander
177971b49872f92239e4e51e9bc549b7
600
http://orcid.org/0000-0001-7408-5084
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-02-03T11:38:00Z
2017-02-03T11:38:00Z
2016
O-Alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-L-selenofucopyranoside. 2016, 12:2828-2833 Beilstein J Org Chem
28144356
10.3762/bjoc.12.282
http://hdl.handle.net/10033/620805
Beilstein journal of organic chemistry
Selenoglycosides are used as reactive glycosyl donors in the syntheses of oligosaccharides. In addition, such heavy atom analogs of natural glycosides are useful tools for structure determination of their lectin receptors using X-ray crystallography. Some lectins, e.g., members of the tectonin family, only bind to carbohydrate epitopes with O-alkylated ring hydroxy groups. In this context, we report the first synthesis of an O-methylated selenoglycoside, specifically methyl 2-O-methyl-L-selenofucopyranoside, a ligand of the lectin tectonin-2 from the mushroom Laccaria bicolor. The synthetic route required a strategic revision and further optimization due to the intrinsic lability of alkyl selenoglycosides, in particular for the labile fucose. Here, we describe a successful synthetic access to methyl 2-O-methyl-L-selenofucopyranoside in 9 linear steps and 26% overall yield starting from allyl L-fucopyranoside.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
O-Alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-L-selenofucopyranoside.
Article
2018-06-12T22:56:38Z
Selenoglycosides are used as reactive glycosyl donors in the syntheses of oligosaccharides. In addition, such heavy atom analogs of natural glycosides are useful tools for structure determination of their lectin receptors using X-ray crystallography. Some lectins, e.g., members of the tectonin family, only bind to carbohydrate epitopes with O-alkylated ring hydroxy groups. In this context, we report the first synthesis of an O-methylated selenoglycoside, specifically methyl 2-O-methyl-L-selenofucopyranoside, a ligand of the lectin tectonin-2 from the mushroom Laccaria bicolor. The synthetic route required a strategic revision and further optimization due to the intrinsic lability of alkyl selenoglycosides, in particular for the labile fucose. Here, we describe a successful synthetic access to methyl 2-O-methyl-L-selenofucopyranoside in 9 linear steps and 26% overall yield starting from allyl L-fucopyranoside.
ORIGINAL
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Helmholtz Zentrum für Infektionsforschung Repository
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oai:repository.helmholtz-hzi.de:10033/6209342019-08-30T11:33:57Zcom_10033_620656col_10033_620658
Torge, Afra
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500
Wagner, Stefanie
935803ea3ccfe8267a16e098ea9a33bc
500
Chaves, Paula S
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Oliveira, Edilene G
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Guterres, Silvia S
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Pohlmann, Adriana R
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500
Titz, Alexander
177971b49872f92239e4e51e9bc549b7
600
http://orcid.org/0000-0001-7408-5084
Schneider, Marc
993f7dd6db902d444eca4004f4281ba2
600
http://orcid.org/0000-0002-9260-7357
Beck, Ruy C R
ab77a720bfc973ddeede49bfa3439184
500
Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-06-06T14:47:00Z
2017-06-06T14:47:00Z
2017-05-10
Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in cystic fibrosis. 2017, 527 (1-2):92-102 Int J Pharm
1873-3476
28499793
10.1016/j.ijpharm.2017.05.013
http://hdl.handle.net/10033/620934
International journal of pharmaceutics
Treatment of bacterial airway infections is essential for cystic fibrosis therapy. However, effectiveness of antibacterial treatment is limited as bacteria inside the mucus are protected from antibiotics and immune response. To overcome this biological barrier, ciprofloxacin was loaded into lipid-core nanocapsules (LNC) for high mucus permeability, sustained release and antibacterial activity. Ciprofloxacin-loaded LNC with a mean size of 180nm showed a by 50% increased drug permeation through mucus. In bacterial growth assays, the drug in the LNC had similar minimum inhibitory concentrations as the free drug in P. aeruginosa and S. aureus. Interestingly, formation of biofilm-like aggregates, which were observed for S. aureus treated with free ciprofloxacin, was avoided by exposure to LNC. With the combined advantages over the non-encapsulated drug, ciprofloxacin-loaded LNC represent a promising drug delivery system with the prospect of an improved antibiotic therapy in cystic fibrosis.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in cystic fibrosis.
Article
2018-07-15T00:00:00Z
Treatment of bacterial airway infections is essential for cystic fibrosis therapy. However, effectiveness of antibacterial treatment is limited as bacteria inside the mucus are protected from antibiotics and immune response. To overcome this biological barrier, ciprofloxacin was loaded into lipid-core nanocapsules (LNC) for high mucus permeability, sustained release and antibacterial activity. Ciprofloxacin-loaded LNC with a mean size of 180nm showed a by 50% increased drug permeation through mucus. In bacterial growth assays, the drug in the LNC had similar minimum inhibitory concentrations as the free drug in P. aeruginosa and S. aureus. Interestingly, formation of biofilm-like aggregates, which were observed for S. aureus treated with free ciprofloxacin, was avoided by exposure to LNC. With the combined advantages over the non-encapsulated drug, ciprofloxacin-loaded LNC represent a promising drug delivery system with the prospect of an improved antibiotic therapy in cystic fibrosis.
ORIGINAL
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hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6211482019-08-30T11:33:29Zcom_10033_620656col_10033_620658
Beshr, Ghamdan
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500
Sikandar, Asfandyar
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500
Jemiller, Eva-Maria
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Klymiuk, Nikolai
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Hauck, Dirk
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Wagner, Stefanie
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Wolf, Eckhard
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Koehnke, Jesko
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Titz, Alexander
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http://orcid.org/0000-0001-7408-5084
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Universitycampus E8.1, 66123 Saarbrücken, Germany.
2017-11-01T10:37:09Z
2017-11-01T10:37:09Z
2017-09-28
Photorhabdus luminescens lectin A (PllA) - a new probe for detecting α-galactoside-terminating glycoconjugates. 2017 J. Biol. Chem.
1083-351X
28972138
10.1074/jbc.M117.812792
http://hdl.handle.net/10033/621148
The Journal of biological chemistry
Lectins play important roles in infections by pathogenic bacteria, for example, in host colonization, persistence and biofilm formation. The Gram-negative entomopathogenic bacterium Photorhabdus luminescens symbiotically lives in insect-infecting Heterorhabditis nematodes and kills the insect host upon invasion by the nematode. The P. luminescens genome harbors the gene plu2096 coding for a novel lectin that we named PllA. We analyzed the binding properties of purified PllA with a glycan array and a binding assay in solution. Both assays revealed a strict specificity of PllA for alpha-galactoside-terminating glycoconjugates. The crystal structures of apo PllA and complexes with three different ligands revealed the molecular basis for the strict specificity of this lectin. Furthermore, we found that a 90 degree twist in subunit orientation leads to a peculiar quaternary structure compared with that of its ortholog LecA from Pseudomonas aeruginosa. We also investigated the utility of PllA as a probe for detecting alpha-galactosides. The alpha-Gal epitope is present on wild-type pig cells and the main reason for hyperacute organ rejection in pig to primate xenotransplantation. We noted that PllA specifically recognizes this epitope on the glycan array and demonstrated that PllA can be used as a fluorescent probe to detect this epitope on primary porcine cells in vitro. In summary, our biochemical and structural analyses of the P. luminescens lectin PllA have disclosed the structural basis for PllAs high specificity for alpha-galactoside-containing ligands, and we show that PllA can be used to visualize alpha-Gal epitope on porcine tissues.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Photorhabdus luminescens lectin A (PllA) - a new probe for detecting α-galactoside-terminating glycoconjugates.
Article
Lectins play important roles in infections by pathogenic bacteria, for example, in host colonization, persistence and biofilm formation. The Gram-negative entomopathogenic bacterium Photorhabdus luminescens symbiotically lives in insect-infecting Heterorhabditis nematodes and kills the insect host upon invasion by the nematode. The P. luminescens genome harbors the gene plu2096 coding for a novel lectin that we named PllA. We analyzed the binding properties of purified PllA with a glycan array and a binding assay in solution. Both assays revealed a strict specificity of PllA for alpha-galactoside-terminating glycoconjugates. The crystal structures of apo PllA and complexes with three different ligands revealed the molecular basis for the strict specificity of this lectin. Furthermore, we found that a 90 degree twist in subunit orientation leads to a peculiar quaternary structure compared with that of its ortholog LecA from Pseudomonas aeruginosa. We also investigated the utility of PllA as a probe for detecting alpha-galactosides. The alpha-Gal epitope is present on wild-type pig cells and the main reason for hyperacute organ rejection in pig to primate xenotransplantation. We noted that PllA specifically recognizes this epitope on the glycan array and demonstrated that PllA can be used as a fluorescent probe to detect this epitope on primary porcine cells in vitro. In summary, our biochemical and structural analyses of the P. luminescens lectin PllA have disclosed the structural basis for PllAs high specificity for alpha-galactoside-containing ligands, and we show that PllA can be used to visualize alpha-Gal epitope on porcine tissues.
ORIGINAL
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Beshr et al.pdf.txt
Beshr et al.pdf.txt
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https://hzi.openrepository.com/bitstream/10033/621148/6/Beshr%20et%20al.pdf.txt
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MD5
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PllA-SI-rev.pdf.txt
PllA-SI-rev.pdf.txt
Extracted Text
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THUMBNAIL
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11
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PllA-SI-rev.pdf.jpg
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10033/621148
oai:hzi.openrepository.com:10033/621148
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oai:repository.helmholtz-hzi.de:10033/6212122019-08-30T11:34:22Zcom_10033_620656com_10033_620618col_10033_620658col_10033_620619
Wagner, Stefanie
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Hauck, Dirk
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Hoffmann, Michael
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Sommer, Roman
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Joachim, Ines
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Müller, Rolf
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http://orcid.org/0000-0002-1042-5665
Imberty, Anne
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Varrot, Annabelle
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Titz, Alexander
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http://orcid.org/0000-0001-7408-5084
HIPS, Helmholtz-Institut für pharmazeutische Forchung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-12-20T10:44:14Z
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
http://creativecommons.org/licenses/by-nc-sa/4.0/
Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging.
Article
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.
ORIGINAL
Wagner et al_.pdf
Wagner et al_.pdf
original manuscript
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supporting information
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CC-LICENSE
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Wagner et al_.pdf.txt
Wagner et al_.pdf.txt
Extracted Text
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MD5
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false
_Epoxides-SupportingInformation_final-experimental-V5.pdf.txt
_Epoxides-SupportingInformation_final-experimental-V5.pdf.txt
Extracted Text
text/plain
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https://hzi.openrepository.com/bitstream/10033/621212/9/_Epoxides-SupportingInformation_final-experimental-V5.pdf.txt
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MD5
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false
THUMBNAIL
Wagner et al_.pdf.jpg
Wagner et al_.pdf.jpg
Generated Thumbnail
image/jpeg
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MD5
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Generated Thumbnail
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2019-08-30 11:34:22.377
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oai:repository.helmholtz-hzi.de:10033/6212642019-08-30T11:31:46Zcom_10033_620656col_10033_620658
Calvert, Matthew B
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Mayer, Christoph
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Titz, Alexander
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Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2018-02-06T14:41:09Z
2018-02-06T14:41:09Z
2017-12-11
An efficient synthesis of 1,6-anhydro- N -acetylmuramic acid from N -acetylglucosamine 2017, 13:2631 Beilstein Journal of Organic Chemistry
1860-5397
30018663
10.3762/bjoc.13.261
http://hdl.handle.net/10033/621264
Beilstein Journal of Organic Chemistry
http://www.beilstein-journals.org/bjoc/content/13/1/261
http://creativecommons.org/licenses/by-nc-sa/4.0/
An efficient synthesis of 1,6-anhydro- N -acetylmuramic acid from N -acetylglucosamine
Article
2018-06-12T23:36:38Z
ORIGINAL
Calvert et al.pdf
Calvert et al.pdf
Open Access publication
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MD5
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CC-LICENSE
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LICENSE
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Calvert et al.pdf.txt
Calvert et al.pdf.txt
Extracted Text
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https://hzi.openrepository.com/bitstream/10033/621264/6/Calvert%20et%20al.pdf.txt
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THUMBNAIL
Calvert et al.pdf.jpg
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Generated Thumbnail
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10033/621264
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2019-08-30 11:31:46.914
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6212922019-08-30T11:36:33Zcom_10033_620656col_10033_620658
Hottmann, Isabel
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Mayer, Valentina M T
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Tomek, Markus B
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Friedrich, Valentin
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Calvert, Matthew B
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Titz, Alexander
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http://orcid.org/0000-0001-7408-5084
Schäffer, Christina
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Mayer, Christoph
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HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus 8.1, 66123 Saarbrücken, Germany.
2018-02-21T14:22:42Z
2018-02-21T14:22:42Z
2018
N-Acetylmuramic Acid (MurNAc) Auxotrophy of the Oral PathogenTannerella forsythia: Characterization of a MurNAc Kinase and Analysis of Its Role in Cell Wall Metabolism. 2018, 9:19 Front Microbiol
1664-302X
29434575
10.3389/fmicb.2018.00019
http://hdl.handle.net/10033/621292
Frontiers in microbiology
Tannerella forsythia is an anaerobic, Gram-negative oral pathogen that thrives in multispecies gingival biofilms associated with periodontitis. The bacterium is auxotrophic for the commonly essential bacterial cell wall sugarN-acetylmuramic acid (MurNAc) and, thus, strictly depends on an exogenous supply of MurNAc for growth and maintenance of cell morphology. A MurNAc transporter (Tf_MurT; Tanf_08375) and an ortholog of theEscherichia colietherase MurQ (Tf_MurQ; Tanf_08385) converting MurNAc-6-phosphate to GlcNAc-6-phosphate were recently described forT. forsythia.In between the respective genes on theT. forsythiagenome, a putative kinase gene is located. In this study, the putative kinase (Tf_MurK; Tanf_08380) was produced as a recombinant protein and biochemically characterized. Kinetic studies revealed Tf_MurK to be a 6-kinase with stringent substrate specificity for MurNAc exhibiting a 6 × 104-fold higher catalytic efficiency (kcat/Km) for MurNAc than forN-acetylglucosamine (GlcNAc) withkcatvalues of 10.5 s-1and 0.1 s-1andKmvalues of 200 μM and 116 mM, respectively. The enzyme kinetic data suggest that Tf_MurK is subject to substrate inhibition (Ki[S]= 4.2 mM). To assess the role of Tf_MurK in the cell wall metabolism ofT. forsythia, a kinase deletion mutant (ΔTf_murK::erm) was constructed. This mutant accumulated MurNAc intracellularly in the exponential phase, indicating the capability to take up MurNAc, but inability to catabolize MurNAc. In the stationary phase, the MurNAc level was reduced in the mutant, while the level of the peptidoglycan precursor UDP-MurNAc-pentapeptide was highly elevated. Further, according to scanning electron microscopy evidence, theΔTf_murK::ermmutant was more tolerant toward low MurNAc concentration in the medium (below 0.5 μg/ml) before transition from healthy, rod-shaped to fusiform cells occurred, while the parent strain required > 1 μg/ml MurNAc for optimal growth. These data reveal thatT. forsythiareadily catabolizes exogenous MurNAc but simultaneously channels a proportion of the sugar into peptidoglycan biosynthesis. Deletion ofTf_murKblocks MurNAc catabolism and allows the direction of MurNAc solely to peptidoglycan biosynthesis, resulting in a growth advantage in MurNAc-depleted medium. This work increases our understanding of theT. forsythiacell wall metabolism and may pave new routes for lead finding in the treatment of periodontitis.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
N-Acetylmuramic Acid (MurNAc) Auxotrophy of the Oral PathogenTannerella forsythia: Characterization of a MurNAc Kinase and Analysis of Its Role in Cell Wall Metabolism.
Article
2018-06-13T05:40:56Z
Tannerella forsythia
is an anaerobic, Gram-negative oral pathogen that thrives in multispecies gingival biofilms associated with periodontitis. The bacterium is auxotrophic for the commonly essential bacterial cell wall sugarN-acetylmuramic acid (MurNAc) and, thus, strictly depends on an exogenous supply of MurNAc for growth and maintenance of cell morphology. A MurNAc transporter (Tf_MurT; Tanf_08375) and an ortholog of theEscherichia colietherase MurQ (Tf_MurQ; Tanf_08385) converting MurNAc-6-phosphate to GlcNAc-6-phosphate were recently described forT. forsythia.In between the respective genes on theT. forsythiagenome, a putative kinase gene is located. In this study, the putative kinase (Tf_MurK; Tanf_08380) was produced as a recombinant protein and biochemically characterized. Kinetic studies revealed Tf_MurK to be a 6-kinase with stringent substrate specificity for MurNAc exhibiting a 6 × 104-fold higher catalytic efficiency (kcat/Km) for MurNAc than forN-acetylglucosamine (GlcNAc) withkcatvalues of 10.5 s-1and 0.1 s-1andKmvalues of 200 μM and 116 mM, respectively. The enzyme kinetic data suggest that Tf_MurK is subject to substrate inhibition (Ki[S]= 4.2 mM). To assess the role of Tf_MurK in the cell wall metabolism ofT. forsythia, a kinase deletion mutant (ΔTf_murK::erm) was constructed. This mutant accumulated MurNAc intracellularly in the exponential phase, indicating the capability to take up MurNAc, but inability to catabolize MurNAc. In the stationary phase, the MurNAc level was reduced in the mutant, while the level of the peptidoglycan precursor UDP-MurNAc-pentapeptide was highly elevated. Further, according to scanning electron microscopy evidence, theΔTf_murK::ermmutant was more tolerant toward low MurNAc concentration in the medium (below 0.5 μg/ml) before transition from healthy, rod-shaped to fusiform cells occurred, while the parent strain required > 1 μg/ml MurNAc for optimal growth. These data reveal thatT. forsythiareadily catabolizes exogenous MurNAc but simultaneously channels a proportion of the sugar into peptidoglycan biosynthesis. Deletion ofTf_murKblocks MurNAc catabolism and allows the direction of MurNAc solely to peptidoglycan biosynthesis, resulting in a growth advantage in MurNAc-depleted medium. This work increases our understanding of theT. forsythiacell wall metabolism and may pave new routes for lead finding in the treatment of periodontitis.
ORIGINAL
Hottmann et al.pdf
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6213662019-08-30T11:25:11Zcom_10033_620656col_10033_620658
Sommer, Roman
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Makshakova, Olga N
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Wohlschlager, Therese
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Hutin, Stephanie
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Marsh, May
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Titz, Alexander
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Künzler, Markus
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Varrot, Annabelle
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HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus 8.1, 66123 Saarbrücken, Germany.
2018-05-07T12:38:06Z
2018-05-07T12:38:06Z
2018-03-06
Crystal Structures of Fungal Tectonin in Complex with O-Methylated Glycans Suggest Key Role in Innate Immune Defense. 2018, 26 (3):391-402.e4 Structure
1878-4186
29398527
10.1016/j.str.2018.01.003
http://hdl.handle.net/10033/621366
Structure (London, England : 1993)
Innate immunity is the first line of defense against pathogens and predators. To initiate a response, it relies on the detection of invaders, where lectin-carbohydrate interactions play a major role. O-Methylated glycans were previously identified as non-self epitopes and conserved targets for defense effector proteins belonging to the tectonin superfamily. Here, we present two crystal structures of Tectonin 2 from the mushroom Laccaria bicolor in complex with methylated ligands, unraveling the molecular basis for this original specificity. Furthermore, they revealed the formation of a ball-shaped tetramer with 24 binding sites distributed at its surface, resembling a small virus capsid. Based on the crystal structures, a methylation recognition motif was identified and found in the sequence of many tectonins from bacteria to human. Our results support a key role of tectonins in innate defense based on a distinctive and conserved type of lectin-glycan interaction.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Crystal Structures of Fungal Tectonin in Complex with O-Methylated Glycans Suggest Key Role in Innate Immune Defense.
Article
2019-03-15T00:00:00Z
Innate immunity is the first line of defense against pathogens and predators. To initiate a response, it relies on the detection of invaders, where lectin-carbohydrate interactions play a major role. O-Methylated glycans were previously identified as non-self epitopes and conserved targets for defense effector proteins belonging to the tectonin superfamily. Here, we present two crystal structures of Tectonin 2 from the mushroom Laccaria bicolor in complex with methylated ligands, unraveling the molecular basis for this original specificity. Furthermore, they revealed the formation of a ball-shaped tetramer with 24 binding sites distributed at its surface, resembling a small virus capsid. Based on the crystal structures, a methylation recognition motif was identified and found in the sequence of many tectonins from bacteria to human. Our results support a key role of tectonins in innate defense based on a distinctive and conserved type of lectin-glycan interaction.
ORIGINAL
Sommer et al.pdf
Sommer et al.pdf
original manuscript
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Helmholtz Zentrum für Infektionsforschung Repository
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oai:repository.helmholtz-hzi.de:10033/6214232019-08-30T11:33:27Zcom_10033_620656col_10033_620658
Sommer, Roman
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Hauck, Dirk
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Titz, Alexander
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HIPS, Helmholtz-Institute für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2018-07-06T08:56:40Z
2018-07-06T08:56:40Z
23656549
10.1002/slct.201700161
http://hdl.handle.net/10033/621423
β‐Linked glycosides of N‐acetyl glucosamine are widespread in nature. Their direct synthesis is hampered by the low reactivity of GlcNAc as a glycosyl donor. We report a selective and rapid copper(II) triflate‐catalyzed two‐step synthesis of β‐glycosides of GlcNAc from cheap GlcNAc as starting material without purification of intermediates. α‐Specific glycosylation can be achieved by increasing the amount of catalyst and extending reaction times.
http://doi.wiley.com/10.1002/slct.201700161
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Efficient Two Step β-Glycoside Synthesis from -Acetyl -Glucosamine: Scope and Limitations of Copper(II) Triflate-Catalyzed Glycosylation
Article
2
15
4187
4192
ChemistrySelect
2018-07-06T08:56:41Z
ORIGINAL
Sommer, Hauck and Titz.pdf
Sommer, Hauck and Titz.pdf
original manuscript
application/pdf
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https://hzi.openrepository.com/bitstream/10033/621423/1/Sommer%2c%20Hauck%20and%20Titz.pdf
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MD5
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supp_info.pdf
supp_info.pdf
supporting information
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https://hzi.openrepository.com/bitstream/10033/621423/2/supp_info.pdf
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MD5
2
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CC-LICENSE
license_rdf
license_rdf
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MD5
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LICENSE
license.txt
license.txt
text/plain
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MD5
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TEXT
Sommer, Hauck and Titz.pdf.txt
Sommer, Hauck and Titz.pdf.txt
Extracted text
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https://hzi.openrepository.com/bitstream/10033/621423/5/Sommer%2c%20Hauck%20and%20Titz.pdf.txt
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MD5
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supp_info.pdf.txt
supp_info.pdf.txt
Extracted text
text/plain
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https://hzi.openrepository.com/bitstream/10033/621423/6/supp_info.pdf.txt
eb93a85bda8806b2e164f92733d29fe9
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THUMBNAIL
Sommer, Hauck and Titz.pdf.jpg
Sommer, Hauck and Titz.pdf.jpg
Generated Thumbnail
image/jpeg
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MD5
7
false
supp_info.pdf.jpg
supp_info.pdf.jpg
Generated Thumbnail
image/jpeg
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https://hzi.openrepository.com/bitstream/10033/621423/8/supp_info.pdf.jpg
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MD5
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10033/621423
oai:hzi.openrepository.com:10033/621423
2019-08-30 11:33:27.194
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6215052018-10-02T01:57:40Zcom_10033_620656col_10033_620658
Calvert, Matthew B
ed0f76ec-903a-4e3b-8a4f-746d871cf893
500
Mayer, Christoph
https://orcid.org/0000-0003-4731-4851
500
Titz, Alexander
0000-0001-7408-5084
500
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus 8.1, 66123 Saarbrücken, Germany.
2018-10-01T13:29:37Z
2018-10-01T13:29:37Z
2017-01-01
1860-5397
30018663
10.3762/bjoc.13.261
http://hdl.handle.net/10033/621505
A novel synthesis of 1,6-anhydro-N-acetylmuramic acid is described, which proceeds in only five steps from the cheap starting material N-acetylglucosamine. This efficient synthesis should enable future studies into the importance of 1,6-anhydromuramic acid in bacterial cell wall recycling processes.
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
N-acetylmuramic acid
05e6ae57-fa16-4da3-b91f-afe53ae77e46
anhydrosugars
5e66c292-fc5b-4463-9c44-a1917b018c75
antibiotic resistance
e0099370-5142-48e6-99dc-59282e5ac979
500
bacterial cell wall recycling
2f72a543-f317-4165-9aa0-e82b068b758a
carbohydrate synthesis
59c4cefe-5c8b-4357-8eb4-134518a775e8
An efficient synthesis of 1,6-anhydro--acetylmuramic acid from -acetylglucosamine.
Article
Beilstein journal of organic chemistry
2018-10-01T13:29:37Z
THUMBNAIL
Calvert, Mayer and Titz.pdf.jpg
Calvert, Mayer and Titz.pdf.jpg
Generated Thumbnail
image/jpeg
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https://hzi.openrepository.com/bitstream/10033/621505/5/Calvert%2c%20Mayer%20and%20Titz.pdf.jpg
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MD5
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TEXT
Calvert, Mayer and Titz.pdf.txt
Calvert, Mayer and Titz.pdf.txt
Extracted text
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LICENSE
license.txt
license.txt
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MD5
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CC-LICENSE
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ORIGINAL
Calvert, Mayer and Titz.pdf
Calvert, Mayer and Titz.pdf
Open Access publication
application/pdf
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MD5
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10033/621505
oai:hzi.openrepository.com:10033/621505
2018-10-02 01:57:40.542
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6215322019-08-30T11:29:40Zcom_10033_620656col_10033_620658
Calvert, Matthew B
621e7a4269427714cca6387f0753a791
500
Jumde, Varsha R
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500
Titz, Alexander
bbe73a0250cae3389056476be5d00d1b
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2018-11-02T11:37:03Z
2018-11-02T11:37:03Z
IPS, Helmholtz-Institut füt Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
1860-5397
10.3762/bjoc.14.239
http://hdl.handle.net/10033/621532
The rapid development of antimicrobial resistance is threatening mankind to such an extent that the World Health Organization expects more deaths from infections than from cancer in 2050 if current trends continue. To avoid this scenario, new classes of anti-infectives must urgently be developed. Antibiotics with new modes of action are needed, but other concepts are also currently being pursued. Targeting bacterial virulence as a means of blocking pathogenicity is a promising new strategy for disarming pathogens. Furthermore, it is believed that this new approach is less susceptible towards resistance development. In this review, recent examples of anti-infective compounds acting on several types of bacterial targets, e.g., adhesins, toxins and bacterial communication, are described.
https://www.beilstein-journals.org/bjoc/articles/14/239
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
antimicrobial resistance
bacterial adhesins
bacterial toxins
pathoblockers
quorum sensing
Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections
Article
14
2607
2617
Beilstein Journal of Organic Chemistry
2018-11-02T11:37:03Z
THUMBNAIL
Calvert et al.pdf.jpg
Calvert et al.pdf.jpg
Generated Thumbnail
image/jpeg
67038
https://hzi.openrepository.com/bitstream/10033/621532/6/Calvert%20et%20al.pdf.jpg
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MD5
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false
TEXT
Calvert et al.pdf.txt
Calvert et al.pdf.txt
Extracted text
text/plain
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oai:repository.helmholtz-hzi.de:10033/6218502019-08-30T11:26:40Zcom_10033_620656col_10033_620658
Lepsik, Martin
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500
Sommer, Roman
ab94b5af1a59bace7c8bfbc08f572b29
500
Kuhaudomlarp, Sakonwan
a5595ebfe6d79b78af98dbe032a181d1
500
Lelimousin, Mickaël
324aa30227ba56dc85a1a6c71d20c419
500
Paci, Emanuele
bacb29e357e0043b6e683f27646ab004
500
Varrot, Annabelle
9f34f205cce62dce96f9cfa8be8d240f
500
Titz, Alexander
177971b49872f92239e4e51e9bc549b7
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http://orcid.org/0000-0001-7408-5084
Imberty, Anne
6e3e5ebf482abdb8033b0c4c8cfa10db
500
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2019-07-08T08:34:30Z
2019-07-08T08:34:30Z
2019-09-01
Eur J Med Chem. 2019 Sep 1;177:212-220. doi: 10.1016/j.ejmech.2019.05.049. Epub 2019 May 18.
1768-3254
31146126
10.1016/j.ejmech.2019.05.049
http://hdl.handle.net/10033/621850
European Journal of Medicinal Chemistry
Pathogenic micro-organisms utilize protein receptors (lectins) in adhesion to host tissues, a process that in some cases relies on the interaction between lectins and human glycoconjugates. Oligosaccharide epitopes are recognized through their three-dimensional structure and their flexibility is a key issue in specificity. In this paper, we analysed by X-ray crystallography the structures of the LecB lectin from two strains of Pseudomonas aeruginosa in complex with Lewis x oligosaccharide present on cell surfaces of human tissues. An unusual conformation of the glycan was observed in all binding sites with a non-canonical syn orientation of the N-acetyl group of N-acetyl-glucosamine. A PDB-wide search revealed that such an orientation occurs only in 4% of protein/carbohydrate complexes. Theoretical chemistry calculations showed that the observed conformation is unstable in solution but stabilised by the lectin. A reliable description of LecB/Lewis x complex by force field-based methods had proven especially challenging due to the special feature of the binding site, two closely apposed Ca2+ ions which induce strong charge delocalisation. By comparing various force-field parametrisations, we propose a general strategy which will be useful in near future for designing carbohydrate-based ligands (glycodrugs) against other calcium-dependent protein receptors.
en
Elsevier
nfo:eu-repo/grantAgreement/EC/H2020/795605
embargoedAccess
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Calcium ion
Carbohydrate
Lectin
Molecular dynamics
N-Acetyl
Quantum effect
Induction of rare conformation of oligosaccharide by binding to calcium-dependent bacterial lectin: X-ray crystallography and modelling study.
Article
European journal of medicinal chemistry
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oai:repository.helmholtz-hzi.de:10033/6219412019-09-17T02:31:02Zcom_10033_620656col_10033_620658
Meiers, Joscha
d40f0789553861e08ffb7c63ef46f8e0
300
Siebs, Eike
d18cc7b8c46777156e28e84caae53176
300
Zahorska, Eva
4fb076edae517f55b0fa92172390bc41
300
Titz, Alexander
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HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2019-09-16T13:38:03Z
2019-09-16T13:38:03Z
2019-08-27
Curr Opin Chem Biol. 2019 Aug 27;53:51-67. doi: 10.1016/j.cbpa.2019.07.005.
1879-0402
31470348
10.1016/j.cbpa.2019.07.005
http://hdl.handle.net/10033/621941
Current Opinion in Chemical Biology
Lectins are proteins found in all domains of life with a plethora of biological functions, especially in the infection process, immune response, and inflammation. Targeting these carbohydrate-binding proteins is challenged by the fact that usually low affinity interactions between lectin and glycoconjugate are observed. Nature often circumvents this process through multivalent display of ligand and lectin. Consequently, the vast majority of synthetic antagonists are multivalently displayed native carbohydrates. At the cost of disadvantageous pharmacokinetic properties and possibly a reduced selectivity for the target lectin, the molecules usually possess very high affinities to the respective lectin through ligand epitope avidity. Recent developments include the advent of glycomimetic or allosteric small molecule inhibitors for this important protein class and their use in chemical biology and drug research. This evolution has culminated in the transition of the small molecule GMI-1070 into clinical phase III. In this opinion article, an overview of the most important developments of lectin antagonists in the last two decades with a focus on the last five years is given
Elsevier
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Lectin antagonists in infection, immunity, and inflammation.
Article
Current opinion in chemical biology
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2020-08-28
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Helmholtz Zentrum für Infektionsforschung Repository
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oai:repository.helmholtz-hzi.de:10033/6219732019-10-12T01:36:28Zcom_10033_620656col_10033_620658
Dingjan, Tamir
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Gillon, Émilie
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Imberty, Anne
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Pérez, Serge
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Titz, Alexander
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http://orcid.org/0000-0001-7408-5084
Ramsland, Paul A
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Yuriev, Elizabeth
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HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2019-10-11T12:03:03Z
2019-10-11T12:03:03Z
2018-09-24
J Chem Inf Model. 2018 Sep 24;58(9):1976-1989. doi: 10.1021/acs.jcim.8b00185. Epub 2018 Sep 4
1549-960X
30075071
10.1021/acs.jcim.8b00185
http://hdl.handle.net/10033/621973
Journal of Chemical Information and Modeling
Bacterial adhesion to human epithelia via lectins constitutes a therapeutic opportunity to prevent infection. Specifically, BambL (the lectin from Burkholderia ambifaria) is implicated in cystic fibrosis, where lectin-mediated bacterial adhesion to fucosylated lung epithelia is suspected to play an important role. We employed structure-based virtual screening to identify inhibitors of BambL-saccharide interaction with potential therapeutic value. To enable such discovery, a virtual screening protocol was iteratively developed via 194 retrospective screening protocols against 4 bacterial lectins (BambL, BC2L-A, FimH, and LecA) with known ligands. Specific attention was given to the rigorous evaluation of retrospective screening, including calculation of analytical errors for enrichment metrics. The developed virtual screening workflow used crystallographic constraints, pharmacophore filters, and a final manual selection step. The protocol was applied to BambL, predicting 15 active compounds from virtual libraries of approximately 7 million compounds. Experimental validation using fluorescence polarization confirmed micromolar inhibitory activity for two compounds, which were further characterized by isothermal titration calorimetry and surface plasmon resonance. Subsequent testing against LecB from Pseudomonas aeruginosa demonstrated binding specificity of one of the hit compounds. This report demonstrates the utility of virtual screening protocols, integrating ligand-based pharmacophore filtering and structure-based constraints, in the search for bacterial lectin inhibitors.
en
American Chemical Society
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Virtual Screening Against Carbohydrate-Binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin.
Article
Journal of chemical information and modeling
THUMBNAIL
2019-11-30
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2019-11-30
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2019-10-12 01:36:28.719
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6219922019-11-08T12:50:04Zcom_10033_620533com_10033_620656col_10033_620534col_10033_620657col_10033_620658
Sommer, Roman
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Rox, Katharina
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Wagner, Stefanie
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Hauck, Dirk
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Henrikus, Sarah S
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Newsad, Shelby
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300
Arnold, Tatjana
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Ryckmans, Thomas
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Brönstrup, Mark
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http://orcid.org/0000-0002-8971-7045
Imberty, Anne
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Varrot, Annabelle
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Hartmann, Rolf W
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Titz, Alexander
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HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-10-28T14:39:28Z
2019-10-28T14:39:28Z
2019-10-24
J Med Chem. 2019 Oct 24;62(20):9201-9216. doi: 10.1021/acs.jmedchem.9b01120. Epub 2019 Oct 11.
1520-4804
31553873
10.1021/acs.jmedchem.9b01120
http://hdl.handle.net/10033/621992
Journal of medicinal Chemistry
Biofilm formation is a key mechanism of antimicrobial resistance. We have recently reported two classes of orally bioavailable C-glycosidic inhibitors of the Pseudomonas aeruginosa lectin LecB with antibiofilm activity. They proved efficient in target binding, were metabolically stable, nontoxic, selective, and potent in inhibiting formation of bacterial biofilm. Here, we designed and synthesized six new carboxamides and 24 new sulfonamides for a detailed structure-activity relationship for two clinically representative LecB variants. Sulfonamides generally showed higher inhibition compared to carboxamides, which was rationalized based on crystal structure analyses. Substitutions at the thiophenesulfonamide increased binding through extensive contacts with a lipophilic protein patch. These metabolically stable compounds showed a further increase in potency toward the target and in biofilm inhibition assays. In general, we established the structure-activity relationship for these promising antibiofilm agents and showed that modification of the sulfonamide residue bears future optimization potential.
en
American Chemical Society
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Anti-biofilm Agents against Pseudomonas aeruginosa: A Structure-Activity Relationship Study of C-Glycosidic LecB Inhibitors
Article
Journal of medicinal chemistry
2019-10-28T14:39:28Z
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10033/621992
oai:repository.helmholtz-hzi.de:10033/621992
2019-11-08 12:50:04.112
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6220752020-01-14T02:20:50Zcom_10033_620656com_10033_620618col_10033_620658col_10033_620619
Siebert, David C B
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Sommer, Roman
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Pogorevc, Domen
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Hoffmann, Michael
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Wenzel, Silke C
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Müller, Rolf
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Titz, Alexander
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600
http://orcid.org/0000-0001-7408-5084
BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
2020-01-13T11:36:10Z
2020-01-13T11:36:10Z
2019-01-01
Beilstein J Org Chem. 2019 Dec 5;15:2922-2929. doi: 10.3762/bjoc.15.286. eCollection 2019.
1860-5397
31839838
10.3762/bjoc.15.286
http://hdl.handle.net/10033/622075
Beilstein Journal of Organic Chemistry
The argyrins are secondary metabolites from myxobacteria with antibiotic activity against Pseudomonas aeruginosa. Studying their structure-activity relationship is hampered by the complexity of the chemical total synthesis. Mutasynthesis is a promising approach where simpler and fully synthetic intermediates of the natural product's biosynthesis can be biotechnologically incorporated. Here, we report the synthesis of a series of tripeptide thioesters as mutasynthons containing the native sequence with a dehydroalanine (Dha) Michael acceptor attached to a sarcosine (Sar) and derivatives. Chemical synthesis of the native sequence ᴅ-Ala-Dha-Sar thioester required revision of the sequential peptide synthesis into a convergent strategy where the thioester with sarcosine was formed before coupling to the Dha-containing dipeptide.
en
Beilstein Institut
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
NRPS
antibiotic
argyrin
mutasynthesis
peptide synthesis
Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis.
Article
Beilstein journal of organic chemistry
2020-01-13T11:36:11Z
THUMBNAIL
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oai:repository.helmholtz-hzi.de:10033/622075
2020-01-14 02:20:50.942
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6223532020-07-16T02:29:08Zcom_10033_620656col_10033_620658
Shanina, Elena
8fc97aed50403100cc7ce1c893a962f4
300
Siebs, Eike
d18cc7b8c46777156e28e84caae53176
500
Zhang, Hengxi
46b4196d0e149914f87776fa34653241
300
Silva, Daniel Varón
016e245f37efc6abf5b5dc219dfb2d0a
300
Joachim, Ines
e3e184873e8376884d46e8a942d2d271
500
Titz, Alexander
bbe73a0250cae3389056476be5d00d1b
500
Rademacher, Christoph
d766fd89c0dcd6c5e4c3962ac148c5db
300
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-07-15T14:07:04Z
2020-07-15T14:07:04Z
2020-06-23
Glycobiology. 2020;cwaa057. doi:10.1093/glycob/cwaa057.
32573695
10.1093/glycob/cwaa057
http://hdl.handle.net/10033/622353
1460-2423
Glycobiology
The carbohydrate-binding protein LecA (PA-IL) from Pseudomonas aeruginosa plays an important role in the formation of biofilms in chronic infections. Development of inhibitors to disrupt LecA-mediated biofilms is desired, but limited to carbohydrate-based ligands. Moreover, discovery of drug-like ligands for LecA is challenging due to its weak affinities. Therefore, we established a protein-observed 19F (PrOF) NMR to probe ligand binding to LecA. LecA was labeled with 5 - fluoroindole to incorporate 5 - fluorotryptophanes and the resonances were assigned by site-directed mutagenesis. This incorporation did not disrupt LecA preference for natural ligands, Ca2+ and d - galactose. Following NMR resonance perturbation of W42, which is located in the carbohydrate-binding region of LecA, allowed to monitor binding of low affinity ligands such as N - acetyl d - galactosamine (d - GalNAc, Kd = 780 ± 97 μM). Moreover, PrOF NMR titration with glycomimetic of LecA p-nitrophenyl β-d-galactoside (pNPGal, Kd = 54 ± 6 μM) demonstrated a six-fold improved binding of d - Gal proving this approach to be valuable for ligand design in future drug discovery campaigns that aim to generate inhibitors of LecA.
en
Oxford Academic
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Drug Discovery
LecA
NMR
Protein-observed 19F NMR of LecA from Pseudomonas aeruginosa.
Article
Glycobiology
England
THUMBNAIL
2021-07-01
Shanina et al.pdf.jpg
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2021-07-01
Shanina et al.pdf.txt
Shanina et al.pdf.txt
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original manuscript
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10033/622353
oai:repository.helmholtz-hzi.de:10033/622353
2020-07-16 02:29:08.818
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6225382020-11-04T04:36:44Zcom_10033_620656col_10033_620657col_10033_620658
Zahorska, Eva
4fb076edae517f55b0fa92172390bc41
500
Kuhaudomlarp, Sakonwan
a5595ebfe6d79b78af98dbe032a181d1
500
Minervini, Saverio
876d95b4a9a448b64eb0eea038f87c8a
300
Yousaf, Sultaan
42d7d4ab297f458a340a765354d385d8
300
Lepsik, Martin
386189402253c57a6d40b9c37256ac7a
500
Kinsinger, Thorsten
44b3220ac0f15c9ca14be2194030814b
300
Hirsch, Anna K H
70f0ddf29d27965af55122735e5b86d2
Imberty, Anne
6e3e5ebf482abdb8033b0c4c8cfa10db
500
Titz, Alexander
177971b49872f92239e4e51e9bc549b7
600
http://orcid.org/0000-0001-7408-5084
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-10-27T10:24:12Z
2020-10-27T10:24:12Z
2020-07-06
Chem Commun (Camb). 2020 Aug 4;56(62):8822-8825. doi: 10.1039/d0cc03490h.
32628229
10.1039/d0cc03490h
http://hdl.handle.net/10033/622538
1364-548X
Chemical communications (Cambridge, England)
Chronic infections with Pseudomonas aeruginosa are associated with the formation of bacterial biofilms. The tetrameric P. aeruginosa lectin LecA is a virulence factor and an anti-biofilm drug target. Increasing the overall binding affinity by multivalent presentation of binding epitopes can enhance the weak carbohydrate-ligand interactions. Low-nanomolar divalent LecA ligands/inhibitors with up to 260-fold valency-normalized potency boost and excellent selectivity over human galectin-1 were synthesized from d-galactose pentaacetate and benzaldehyde-based linkers in four linear steps.
en
Royal Sciety of Chemistry
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d-galactose pentaacetate.
Article
56
62
8822
8825
Chemical communications (Cambridge, England)
England
2020-10-27T10:24:12Z
THUMBNAIL
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Zahorska et al.pdf.txt
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10033/622538
oai:repository.helmholtz-hzi.de:10033/622538
2020-11-04 04:36:44.155
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6226202021-07-26T11:56:41Zcom_10033_620656col_10033_620657col_10033_620658
Meiers, Joscha
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500
Zahorska, Eva
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500
Röhrig, Teresa
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Hauck, Dirk
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Wagner, Stefanie
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Titz, Alexander
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500
http://orcid.org/0000-0001-7408-5084
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-11-27T15:02:09Z
2020-11-27T15:02:09Z
2020-10-02
J Med Chem. 2020 Oct 22;63(20):11707-11724. doi: 10.1021/acs.jmedchem.0c00856. Epub 2020 Oct 2.
32924479
10.1021/acs.jmedchem.0c00856
http://hdl.handle.net/10033/622620
1520-4804
Journal of medicinal chemistry
Chronic infections by Pseudomonas aeruginosa are characterized by biofilm formation, which effectively enhances resistance toward antibiotics. Biofilm-specific antibiotic delivery could locally increase drug concentration to break antimicrobial resistance and reduce the drug's peripheral side effects. Two extracellular P. aeruginosa lectins, LecA and LecB, are essential structural components for biofilm formation and thus render a possible anchor for biofilm-targeted drug delivery. The standard-of-care drug ciprofloxacin suffers from severe systemic side effects and was therefore chosen for this approach. We synthesized several ciprofloxacin-carbohydrate conjugates and established a structure-activity relationship. Conjugation of ciprofloxacin to lectin probes enabled biofilm accumulation in vitro, reduced the antibiotic's cytotoxicity, but also reduced its antibiotic activity against planktonic cells due to a reduced cell permeability and on target activity. This work defines the starting point for new biofilm/lectin-targeted drugs to modulate antibiotic properties and ultimately break antimicrobial resistance.
en
ACS
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Directing Drugs to Bugs: Antibiotic-Carbohydrate Conjugates Targeting Biofilm-Associated Lectins of Pseudomonas aeruginosa .
Article
63
20
11707
11724
Journal of medicinal chemistry
United States
2020-11-27T15:02:10Z
THUMBNAIL
Meiers et al.pdf.jpg
Meiers et al.pdf.jpg
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ORIGINAL
Meiers et al.pdf
Meiers et al.pdf
free PMC file
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MD5
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true
LICENSE
license.txt
license.txt
text/plain
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CC-LICENSE
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https://repository.helmholtz-hzi.de/bitstream/10033/622620/2/license_rdf
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MD5
2
false
10033/622620
oai:repository.helmholtz-hzi.de:10033/622620
2021-07-26 11:56:41.206
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6228442021-04-28T01:38:45Zcom_10033_620656col_10033_620658
Kuhaudomlarp, Sakonwan
a5595ebfe6d79b78af98dbe032a181d1
500
Siebs, Eike
d18cc7b8c46777156e28e84caae53176
500
Shanina, Elena
8fc97aed50403100cc7ce1c893a962f4
500
Topin, Jérémie
0b53a5c9035e7c2ff4fbd83b4d4703fc
300
Joachim, Ines
e3e184873e8376884d46e8a942d2d271
500
da Silva Figueiredo Celestino Gomes, Priscila
a627f3999cc787aaadf6362d084df9ca
300
Varrot, Annabelle
9f34f205cce62dce96f9cfa8be8d240f
500
Rognan, Didier
6198877c7de693243cf9c8e11aaf9b2e
300
Rademacher, Christoph
d766fd89c0dcd6c5e4c3962ac148c5db
500
Imberty, Anne
6e3e5ebf482abdb8033b0c4c8cfa10db
500
Titz, Alexander
177971b49872f92239e4e51e9bc549b7
600
http://orcid.org/0000-0001-7408-5084
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-04-27T11:40:29Z
2021-04-27T11:40:29Z
2021-03-03
Angew Chem Int Ed Engl. 2021 Apr 6;60(15):8104-8114. doi: 10.1002/anie.202013217. Epub 2021 Mar 3.
33314528
10.1002/anie.202013217
http://hdl.handle.net/10033/622844
1521-3773
Angewandte Chemie (International ed. in English)
Because of the antimicrobial resistance crisis, lectins are considered novel drug targets. Pseudomonas aeruginosa utilizes LecA and LecB in the infection process. Inhibition of both lectins with carbohydrate-derived molecules can reduce biofilm formation to restore antimicrobial susceptibility. Here, we focused on non-carbohydrate inhibitors for LecA to explore new avenues for lectin inhibition. From a screening cascade we obtained one experimentally confirmed hit, a catechol, belonging to the well-known PAINS compounds. Rigorous analyses validated electron-deficient catechols as millimolar LecA inhibitors. The first co-crystal structure of a non-carbohydrate inhibitor in complex with a bacterial lectin clearly demonstrates the catechol mimicking the binding of natural glycosides with LecA. Importantly, catechol 3 is the first non-carbohydrate lectin ligand that binds bacterial and mammalian calcium(II)-binding lectins, giving rise to this fundamentally new class of glycomimetics.
en
Wiley-VCH
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
PAINS
carbohydrates
catechol
glycomimetic
lectin
Non-Carbohydrate Glycomimetics as Inhibitors of Calcium(II)-Binding Lectins.
Article
60
15
8104
8114
Angewandte Chemie (International ed. in English)
Germany
2021-04-27T11:40:29Z
THUMBNAIL
Kuhaudomlarp et al.pdf.jpg
Kuhaudomlarp et al.pdf.jpg
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MD5
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false
TEXT
Kuhaudomlarp et al.pdf.txt
Kuhaudomlarp et al.pdf.txt
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MD5
4
false
LICENSE
license.txt
license.txt
text/plain
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cb598eeb10bfed09d26fd8d285172ad4
MD5
3
false
CC-LICENSE
license_rdf
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908
https://repository.helmholtz-hzi.de/bitstream/10033/622844/2/license_rdf
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MD5
2
false
ORIGINAL
Kuhaudomlarp et al.pdf
Kuhaudomlarp et al.pdf
Open Access publication
application/pdf
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https://repository.helmholtz-hzi.de/bitstream/10033/622844/1/Kuhaudomlarp%20et%20al.pdf
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MD5
1
true
10033/622844
oai:repository.helmholtz-hzi.de:10033/622844
2021-04-28 01:38:45.251
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6229292021-07-09T01:45:38Zcom_10033_620656col_10033_620658
Wohlschlager, Therese
99fe8a12cf30b6f803e78bf0259a3504
500
Titz, Alexander
bbe73a0250cae3389056476be5d00d1b
500
Künzler, Markus
3a9da4fff2b338b85cb9efa2a54263f9
500
Varrot, Annabelle
9f34f205cce62dce96f9cfa8be8d240f
500
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-07-08T09:26:13Z
2021-07-08T09:26:13Z
2020-04-19
Methods Mol Biol. 2020;2132:669-682. doi: 10.1007/978-1-0716-0430-4_58.
32306366
10.1007/978-1-0716-0430-4_58
http://hdl.handle.net/10033/622929
1940-6029
Methods in molecular biology (Clifton, N.J.)
Tectonins are conserved defense proteins of innate immune systems featuring a β-propeller fold. Tectonin 2 from Laccaria bicolor, Lb-Tec2, is the first fungal representative of the tectonin superfamily that has been described. In-depth characterization revealed a specificity for O-methylated glycans and identified a unique sequence motif and binding site architecture underlying this unusual specificity. This chapter provides information on how to produce and purify recombinant Lb-Tec2, characterize its interaction with O-methylated glycans and demonstrate its biological function.
en
Springer
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Defense effector
Innate immunity
Nematotoxic lectin
Non-self recognition
O-Methylated glycans
β-Propeller
Expression, Purification, and Functional Characterization of Tectonin 2 from Laccaria bicolor: A Six-Bladed Beta-Propeller Lectin Specific for O-Methylated Glycans.
Article
2132
669
682
Methods in molecular biology (Clifton, N.J.)
United States
2021-07-08T09:26:13Z
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oai:repository.helmholtz-hzi.de:10033/6229572021-10-06T01:56:22Zcom_10033_620656col_10033_620658
Müller, Maraike
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300
Calvert, Matthew
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Hottmann, Isabel
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500
Kluj, Robert Maria
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300
Teufel, Tim
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300
Balbuchta, Katja
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300
Engelbrecht, Alicia
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Selim, Khaled A
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Xu, Qingping
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Borisova, Marina
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Titz, Alexander
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http://orcid.org/0000-0001-7408-5084
Mayer, Christoph
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500
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-07-23T13:59:50Z
2021-07-23T13:59:50Z
2021-03-05
J Biol Chem. 2021 Jan-Jun;296:100519. doi: 10.1016/j.jbc.2021.100519. Epub 2021 Mar 5.
33684445
10.1016/j.jbc.2021.100519
http://hdl.handle.net/10033/622957
1083-351X
The Journal of biological chemistry
Endo-β-N-acetylmuramidases, commonly known as lysozymes, are well-characterized antimicrobial enzymes that catalyze an endo-lytic cleavage of peptidoglycan; i.e., they hydrolyze the β-1,4-glycosidic bonds connecting N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (GlcNAc). In contrast, little is known about exo-β-N-acetylmuramidases, which catalyze an exo-lytic cleavage of β-1,4-MurNAc entities from the non-reducing ends of peptidoglycan chains. Such an enzyme was identified earlier in the bacterium Bacillus subtilis, but the corresponding gene has remained unknown so far. We now report that ybbC of B. subtilis, renamed namZ, encodes the reported exo-β-N-acetylmuramidase. A ΔnamZ mutant accumulated specific cell wall fragments and showed growth defects under starvation conditions, indicating a role of NamZ in cell wall turnover and recycling. Recombinant NamZ protein specifically hydrolyzed the artificial substrate para-nitrophenyl β-MurNAc and the peptidoglycan-derived disaccharide MurNAc-β-1,4-GlcNAc. Together with the exo-β-N-acetylglucosaminidase NagZ and the exo-muramoyl-l-alanine amidase AmiE, NamZ degraded intact peptidoglycan by sequential hydrolysis from the non-reducing ends. A structure model of NamZ, built on the basis of two crystal structures of putative orthologs from Bacteroides fragilis, revealed a two-domain structure including a Rossmann-fold-like domain that constitutes a unique glycosidase fold. Thus, NamZ, a member of the DUF1343 protein family of unknown function, is now classified as the founding member of a new family of glycosidases (CAZy GH171; www.cazy.org/GH171.html). NamZ-like peptidoglycan hexosaminidases are mainly present in the phylum Bacteroidetes and less frequently found in individual genomes within Firmicutes (Bacilli, Clostridia), Actinobacteria, and γ-proteobacteria.
en
Elsevier
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
N-acetylglucosaminidase
N-acetylmuramidase
N-acetylmuramoyl amidase
Rossmann-fold
cell wall recycling
exo-lytic glycosidase
lysozyme
peptidoglycan hydrolase
The exo-β-N-acetylmuramidase NamZ from Bacillus subtilis is the founding member of a family of exo-lytic peptidoglycan hexosaminidases.
Article
296
100519
The Journal of biological chemistry
United States
2021-07-23T13:59:50Z
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