A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB.

2.50
Hdl Handle:
http://hdl.handle.net/10033/336587
Title:
A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB.
Authors:
Sommer, Roman; Exner, Thomas E; Titz, Alexander
Abstract:
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.
Affiliation:
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.
Citation:
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
Journal:
PloS one
Issue Date:
2014
URI:
http://hdl.handle.net/10033/336587
DOI:
10.1371/journal.pone.0112822
PubMed ID:
25415418
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the junior research group chemical biology of carbohydrates ([HIPS]CBCH)

Full metadata record

DC FieldValue Language
dc.contributor.authorSommer, Romanen
dc.contributor.authorExner, Thomas Een
dc.contributor.authorTitz, Alexanderen
dc.date.accessioned2014-12-04T10:46:13Z-
dc.date.available2014-12-04T10:46:13Z-
dc.date.issued2014-
dc.identifier.citationA Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB. 2014, 9 (11):e112822 PLoS ONEen
dc.identifier.issn1932-6203-
dc.identifier.pmid25415418-
dc.identifier.doi10.1371/journal.pone.0112822-
dc.identifier.urihttp://hdl.handle.net/10033/336587-
dc.description.abstractThe 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
dc.language.isoenen
dc.titleA Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB.en
dc.typeArticleen
dc.contributor.departmentHelmholtz 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.en
dc.identifier.journalPloS oneen

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