Titre :

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

Auteur(s) :

Mousavifar, Leila [Auteur]
Université du Québec à Montréal = University of Québec in Montréal [UQAM]
Sarshar, Meysam [Auteur]

Bridot, Clarisse [Auteur]
Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167
Scribano, Daniela [Auteur]
Ambrosi, Cecilia [Auteur]
Palamara, Anna Teresa [Auteur]
Vergoten, Gérard [Auteur]
Roubinet, Benoît [Auteur]
Landemarre, Ludovic [Auteur]
Bouckaert, Julie [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Roy, René [Auteur]

Titre de la revue :

Pharmaceutics

Nom court de la revue :

Pharmaceutics

Numéro :

15

Pagination :

527

Éditeur :

MDPI AG

Date de publication :

2023-02-04

ISSN :

1999-4923

Mot(s)-clé(s) en anglais :

uropathogenic Escherichia coli (UPEC)
FimH
antagonists
mannosides
glycocomimetics
crystallography
adhesion inhibition
bladder cells
molecular dynamic simulations

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

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 ...
Lire la suite >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.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

Université de Lille
CNRS

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Équipe(s) de recherche :

Computational Molecular Systems Biology

Date de dépôt :

2023-04-04T14:20:31Z
2023-04-05T07:04:34Z