Title :

Heptyl α-D-mannosides grafted on a β-cyclodextrin core to interfere with Escherichia coli adhesion: an in vivo multivalent effect

Author(s) :

Bouckaert, Julie [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Li, Zhaoli [Auteur]

Xavier, Catarina [Auteur]

Almant, Mehdi [Auteur]
Laboratoire des Glucides [LG]
Caveliers, Vicky [Auteur]

Lahoutte, Tony [Auteur]

Weeks, Stephen D. [Auteur]
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven
Kovensky, José [Auteur]
Laboratoire des Glucides [LG]
Gouin, Sébastien G. [Auteur]
Laboratoire des Glucides [LG]

Journal title :

Chemistry (Weinheim an der Bergstrasse, Germany)

Abbreviated title :

Chemistry

Volume number :

19

Pages :

7847-7855

Publication date :

2013-06-10

ISSN :

1521-3765

English keyword(s) :

Anti-Bacterial Agents
Fimbriae Proteins
Fimbriae, Bacterial
Mannosides
Animals
beta-Cyclodextrins
Adhesins, Escherichia coli
Click Chemistry
Models, Biological
Escherichia coli
Calorimetry
Mice

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [en]

n-Heptyl α-D-mannoside (HM) has previously been identified as a nanomolar FimH antagonist able to prevent Escherichia coli adhesion. We have designed mono- and heptavalent glycoconjugates in which HM is tethered to ...
Show more >n-Heptyl α-D-mannoside (HM) has previously been identified as a nanomolar FimH antagonist able to prevent Escherichia coli adhesion. We have designed mono- and heptavalent glycoconjugates in which HM is tethered to β-cyclodextrin (β-CD) through short and long spacers. One-pot click or co-clicking procedures were developed to directly obtain the glycoconjugates from unprotected HM and β-CD precursors. These FimH antagonists were examined biophysically and in vivo. Reverse titrations by isothermal calorimetry led to trapping of the short-tethered heptavalent β-CD in a complex with three FimH lectins. Combined dynamic light scattering and small-angle X-ray solution scattering data allowed the construction of a model of the FimH trimer. The heptavalent β-CDs were shown to capture and aggregate living bacteria in solution and are therefore also able to aggregate FimH when attached to different bacteria pili. The first in vivo evaluation of multivalent FimH inhibitors has been performed. The heptavalent β-CDs proved to be much more effective anti-adhesive agents than monovalent references with doses of around 2 μg instilled in the mouse bladder leading to a significantly decreased E. coli load. Intravenously injected radiolabeled glycoconjugates can rapidly reach the mouse bladder and >2 μg concentrations can easily be retained over 24 h to prevent fluxing bacteria from rebinding.Show less >

Language :

Anglais

Audience :

Non spécifiée

Administrative institution(s) :

CNRS
Université de Lille

Collections :

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

Research team(s) :

Chemical Glycobiology

Submission date :

2020-02-12T15:11:07Z
2021-05-05T09:21:37Z