Titre :

Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive Escherichia coli Bacteria Associated with Crohn's Disease

Auteur(s) :

Sivignon, Adeline [Auteur]
Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte [M2iSH]
Yan, Xibo [Auteur]
Ingénierie des Matériaux Polymères [IMP]
Alvarez Dorta, Dimitri [Auteur]
Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation [CEISAM]
Bonnet, Richard [Auteur]
Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte [M2iSH]
Bouckaert, Julie [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Fleury, Etienne [Auteur]
Ingénierie des Matériaux Polymères [IMP]
Bernard, Julien [Auteur]
Ingénierie des Matériaux Polymères [IMP]
Gouin, Sébastien G. [Auteur]
Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation [CEISAM]
Darfeuille-Michaud, Arlette [Auteur]
Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte [M2iSH]
Barnich, Nicolas [Auteur]
Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte [M2iSH]

Titre de la revue :

mBio

Nom court de la revue :

MBio

Numéro :

6

Pagination :

e01298-01215

Date de publication :

2015-11-17

ISSN :

2150-7511

Mot(s)-clé(s) en anglais :

Intestinal Mucosa
Fimbriae Proteins
Fimbriae, Bacterial
Mannosides
Intestines
Escherichia coli Infection
Glycoconjugates
Adhesins, Escherichia coli
Administration, Oral
Cell Adhesion Molecules
Escherichia coli
GPI-Linked Proteins
Crohn Disease
Epithelial Cells
Bacterial Load
Drug Discovery
Bacterial Adhesion
Animals
beta-Cyclodextrins
Mice
Feces
Antigens, CD

Discipline(s) HAL :

Chimie/Chimie théorique et/ou physique

Résumé en anglais : [en]

The ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasive Escherichia coli (AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent ...
Lire la suite >The ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasive Escherichia coli (AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent manner. In this study, we investigated different antagonists of FimH, the adhesin of type 1 pili, for their ability to block AIEC adhesion to intestinal epithelial cells (IEC). Monovalent and multivalent derivatives of n-heptyl α-d-mannoside (HM), a nanomolar antagonist of FimH, were tested in vitro in IEC infected with the AIEC LF82 strain and in vivo by oral administration to CEACAM6-expressing mice infected with LF82 bacteria. In vitro, multivalent derivatives were more potent than the monovalent derivatives, with a gain of efficacy superior to their valencies, probably owing to their ability to form bacterial aggregates. Of note, HM and the multi-HM glycoconjugates exhibited lower efficacy in vivo in decreasing LF82 gut colonization. Interestingly, HM analogues functionalized with an isopropylamide (1A-HM) or β-cyclodextrin pharmacophore at the end of the heptyl tail (1CD-HM) exerted beneficial effects in vivo. These two compounds strongly decreased the amount of LF82 bacteria in the feces of mice and that of bacteria associated with the gut mucosa when administered orally at a dose of 10 mg/kg of body weight after infection. Importantly, signs of colitis and intestinal inflammation induced by LF82 infection were also prevented. These results highlight the potential of the antiadhesive compounds to treat CD patients abnormally colonized by AIEC bacteria and point to an alternative to the current approach focusing on blocking proinflammatory mediators. IMPORTANCE: Current treatments for Crohn's disease (CD), including immunosuppressive agents, anti-tumor necrosis factor alpha (anti-TNF-α) and anti-integrin antibodies, focus on the symptoms but not on the cause of the disease. Adherent-invasive Escherichia coli (AIEC) bacteria abnormally colonize the ileal mucosa of CD patients via the interaction of the mannose-specific adhesin FimH of type 1 pili with CEACAM6 mannosylated proteins expressed on the epithelial cell surface. Thus, we decided to develop an antiadhesive strategy based on synthetic FimH antagonists specifically targeting AIEC bacteria that would decrease intestinal inflammation. Heptylmannoside (HM)-based glycocompounds strongly inhibit AIEC adhesion to intestinal epithelial cells in vitro. The antiadhesive effect of two of these compounds of relatively simple chemical structure was also observed in vivo in AIEC-infected CEACAM6-expressing mice and was associated with a reduction in the signs of colitis. These results suggest a new therapeutic approach for CD patients colonized by AIEC bacteria, based on the development of synthetic FimH antagonists.Lire moins >

Langue :

Anglais

Audience :

Non spécifiée

Projet ANR :

Effets thérapeutiques de polymères mannosylés synthétiques capables de contrôler les infections chroniques ntestinales à Escherichia coli en interagissant avec la dynamique de glycosylation des cellules hôtes

Établissement(s) :

CNRS
Université de Lille

Collections :

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

Équipe(s) de recherche :

Computational Molecular Systems Biology

Date de dépôt :

2020-02-12T15:11:17Z
2021-03-26T10:18:21Z