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

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 bacte...

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Main Authors:	Sommer, Roman, Exner, Thomas E., Titz, Alexander
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240550/

id	pubmed-4240550
recordtype	oai_dc
spelling	pubmed-42405502014-11-26 A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB Sommer, Roman Exner, Thomas E. Titz, Alexander Research Article 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. Public Library of Science 2014-11-21 /pmc/articles/PMC4240550/ /pubmed/25415418 http://dx.doi.org/10.1371/journal.pone.0112822 Text en © 2014 Sommer et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Sommer, Roman Exner, Thomas E. Titz, Alexander
spellingShingle	Sommer, Roman Exner, Thomas E. Titz, Alexander A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB
author_facet	Sommer, Roman Exner, Thomas E. Titz, Alexander
author_sort	Sommer, Roman
title	A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB
title_short	A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB
title_full	A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB
title_fullStr	A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB
title_full_unstemmed	A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB
title_sort	biophysical study with carbohydrate derivatives explains the molecular basis of monosaccharide selectivity of the pseudomonas aeruginosa lectin lecb
description	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.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240550/
_version_	1613159647053611008

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

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