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Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists

Selective antiadhesion antagonists of Uropathogenic Escherichia coli (UPEC) type-1 Fimbrial adhesin (FimH) are attractive alternatives for antibiotic therapies and prophylaxes against acute or recurrent urinary tract infections (UTIs) caused by UPECs. A rational small library of FimH antagonists bas...

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Autores principales: Mousavifar, Leila, Sarshar, Meysam, Bridot, Clarisse, Scribano, Daniela, Ambrosi, Cecilia, Palamara, Anna Teresa, Vergoten, Gérard, Roubinet, Benoît, Landemarre, Ludovic, Bouckaert, Julie, Roy, René
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9962304/
https://www.ncbi.nlm.nih.gov/pubmed/36839848
http://dx.doi.org/10.3390/pharmaceutics15020527
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author Mousavifar, Leila
Sarshar, Meysam
Bridot, Clarisse
Scribano, Daniela
Ambrosi, Cecilia
Palamara, Anna Teresa
Vergoten, Gérard
Roubinet, Benoît
Landemarre, Ludovic
Bouckaert, Julie
Roy, René
author_facet Mousavifar, Leila
Sarshar, Meysam
Bridot, Clarisse
Scribano, Daniela
Ambrosi, Cecilia
Palamara, Anna Teresa
Vergoten, Gérard
Roubinet, Benoît
Landemarre, Ludovic
Bouckaert, Julie
Roy, René
author_sort Mousavifar, Leila
collection PubMed
description Selective antiadhesion antagonists of Uropathogenic Escherichia coli (UPEC) type-1 Fimbrial adhesin (FimH) are attractive alternatives for antibiotic therapies and prophylaxes against acute or recurrent urinary tract infections (UTIs) caused by UPECs. A rational small library of FimH antagonists based on previously described C-linked allyl α-D-mannopyranoside was synthesized using Heck cross-coupling reaction using a series of iodoaryl derivatives. This work reports two new members of FimH antagonist amongst the above family with sub nanomolar affinity. The resulting hydrophobic aglycones, including constrained alkene and aryl groups, were designed to provide additional favorable binding interactions with the so-called FimH “tyrosine gate”. The newly synthesized C-linked glycomimetic antagonists, having a hydrolytically stable anomeric linkage, exhibited improved binding when compared to previously published analogs, as demonstrated by affinity measurement through interactions by FimH lectin. The crystal structure of FimH co-crystallized with one of the nanomolar antagonists revealed the binding mode of this inhibitor into the active site of the tyrosine gate. In addition, selected mannopyranoside constructs neither affected bacterial growth or cell viability nor interfered with antibiotic activity. C-linked mannoside antagonists were effective in decreasing bacterial adhesion to human bladder epithelial cells (HTB-9). Therefore, these molecules constituted additional therapeutic candidates’ worth further development in the search for potent anti-adhesive drugs against infections caused by UPEC.
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spelling pubmed-99623042023-02-26 Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists Mousavifar, Leila Sarshar, Meysam Bridot, Clarisse Scribano, Daniela Ambrosi, Cecilia Palamara, Anna Teresa Vergoten, Gérard Roubinet, Benoît Landemarre, Ludovic Bouckaert, Julie Roy, René Pharmaceutics Article Selective antiadhesion antagonists of Uropathogenic Escherichia coli (UPEC) type-1 Fimbrial adhesin (FimH) are attractive alternatives for antibiotic therapies and prophylaxes against acute or recurrent urinary tract infections (UTIs) caused by UPECs. A rational small library of FimH antagonists based on previously described C-linked allyl α-D-mannopyranoside was synthesized using Heck cross-coupling reaction using a series of iodoaryl derivatives. This work reports two new members of FimH antagonist amongst the above family with sub nanomolar affinity. The resulting hydrophobic aglycones, including constrained alkene and aryl groups, were designed to provide additional favorable binding interactions with the so-called FimH “tyrosine gate”. The newly synthesized C-linked glycomimetic antagonists, having a hydrolytically stable anomeric linkage, exhibited improved binding when compared to previously published analogs, as demonstrated by affinity measurement through interactions by FimH lectin. The crystal structure of FimH co-crystallized with one of the nanomolar antagonists revealed the binding mode of this inhibitor into the active site of the tyrosine gate. In addition, selected mannopyranoside constructs neither affected bacterial growth or cell viability nor interfered with antibiotic activity. C-linked mannoside antagonists were effective in decreasing bacterial adhesion to human bladder epithelial cells (HTB-9). Therefore, these molecules constituted additional therapeutic candidates’ worth further development in the search for potent anti-adhesive drugs against infections caused by UPEC. MDPI 2023-02-04 /pmc/articles/PMC9962304/ /pubmed/36839848 http://dx.doi.org/10.3390/pharmaceutics15020527 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mousavifar, Leila
Sarshar, Meysam
Bridot, Clarisse
Scribano, Daniela
Ambrosi, Cecilia
Palamara, Anna Teresa
Vergoten, Gérard
Roubinet, Benoît
Landemarre, Ludovic
Bouckaert, Julie
Roy, René
Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists
title Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists
title_full Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists
title_fullStr Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists
title_full_unstemmed Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists
title_short Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists
title_sort insightful improvement in the design of potent uropathogenic e. coli fimh antagonists
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9962304/
https://www.ncbi.nlm.nih.gov/pubmed/36839848
http://dx.doi.org/10.3390/pharmaceutics15020527
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