PMID- 26578673 OWN - NLM STAT- MEDLINE DCOM- 20160816 LR - 20191227 IS - 2150-7511 (Electronic) VI - 6 IP - 6 DP - 2015 Nov 17 TI - Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive Escherichia coli Bacteria Associated with Crohn's Disease. PG - e01298-15 LID - 10.1128/mBio.01298-15 [doi] LID - e01298-15 AB - 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 alpha-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 beta-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-alpha) 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. CI - Copyright (c) 2015 Sivignon et al. FAU - Sivignon, Adeline AU - Sivignon A AD - Clermont Universite, UMR 1071 INSERM/Universite d'Auvergne, Clermont-Ferrand, France INRA, Unite Sous Contrat 2018, Clermont-Ferrand, France. FAU - Yan, Xibo AU - Yan X AD - Universite de Lyon, Lyon, France INSA-Lyon, Ingenierie des Materiaux Polymeres (IMP), Villeurbanne, France CNRS, UMR 5223, Ingenierie des Materiaux Polymeres, Villeurbanne, France. FAU - Alvarez Dorta, Dimitri AU - Alvarez Dorta D AD - LUNAM Universite, Chimie et Interdisciplinarite, Synthese, Analyse, Modelisation (CEISAM), UMR CNRS 6230, UFR des Sciences et des Techniques, Nantes, France. FAU - Bonnet, Richard AU - Bonnet R AD - Clermont Universite, UMR 1071 INSERM/Universite d'Auvergne, Clermont-Ferrand, France INRA, Unite Sous Contrat 2018, Clermont-Ferrand, France Centre Hospitalier Universitaire, Clermont-Ferrand, France. FAU - Bouckaert, Julie AU - Bouckaert J AD - Unite de Glycobiologie Structurale et Fonctionnelle (UGSF), UMR8576, CNRS, Universite Lille 1, Lille, France. FAU - Fleury, Etienne AU - Fleury E AD - Universite de Lyon, Lyon, France INSA-Lyon, Ingenierie des Materiaux Polymeres (IMP), Villeurbanne, France CNRS, UMR 5223, Ingenierie des Materiaux Polymeres, Villeurbanne, France. FAU - Bernard, Julien AU - Bernard J AD - Universite de Lyon, Lyon, France INSA-Lyon, Ingenierie des Materiaux Polymeres (IMP), Villeurbanne, France CNRS, UMR 5223, Ingenierie des Materiaux Polymeres, Villeurbanne, France. FAU - Gouin, Sebastien G AU - Gouin SG AD - LUNAM Universite, Chimie et Interdisciplinarite, Synthese, Analyse, Modelisation (CEISAM), UMR CNRS 6230, UFR des Sciences et des Techniques, Nantes, France. FAU - Darfeuille-Michaud, Arlette AU - Darfeuille-Michaud A AD - Clermont Universite, UMR 1071 INSERM/Universite d'Auvergne, Clermont-Ferrand, France INRA, Unite Sous Contrat 2018, Clermont-Ferrand, France. FAU - Barnich, Nicolas AU - Barnich N AD - Clermont Universite, UMR 1071 INSERM/Universite d'Auvergne, Clermont-Ferrand, France INRA, Unite Sous Contrat 2018, Clermont-Ferrand, France nicolas.barnich@udamail.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151117 PL - United States TA - mBio JT - mBio JID - 101519231 RN - 0 (Adhesins, Escherichia coli) RN - 0 (Antigens, CD) RN - 0 (Cell Adhesion Molecules) RN - 0 (GPI-Linked Proteins) RN - 0 (Glycoconjugates) RN - 0 (Gm5893 protein, mouse) RN - 0 (Mannosides) RN - 0 (beta-Cyclodextrins) RN - 0 (fimH protein, E coli) RN - 147680-16-8 (Fimbriae Proteins) RN - JV039JZZ3A (betadex) SB - IM MH - Adhesins, Escherichia coli MH - Administration, Oral MH - Animals MH - Antigens, CD/genetics/metabolism MH - Bacterial Adhesion/*drug effects MH - Bacterial Load MH - Cell Adhesion Molecules/genetics/metabolism MH - Crohn Disease/*microbiology MH - Drug Discovery MH - Epithelial Cells/drug effects/microbiology MH - Escherichia coli/*drug effects/growth & development/physiology MH - Escherichia coli Infections/*drug therapy/microbiology MH - Feces/microbiology MH - Fimbriae Proteins/antagonists & inhibitors MH - Fimbriae, Bacterial/metabolism MH - GPI-Linked Proteins/genetics/metabolism MH - Glycoconjugates/chemistry/*therapeutic use MH - Intestinal Mucosa/drug effects/metabolism/microbiology MH - Intestines/cytology/microbiology MH - Mannosides/chemical synthesis/chemistry/pharmacology/*therapeutic use MH - Mice MH - beta-Cyclodextrins PMC - PMC4659459 EDAT- 2015/11/19 06:00 MHDA- 2016/08/17 06:00 PMCR- 2015/11/17 CRDT- 2015/11/19 06:00 PHST- 2015/11/19 06:00 [entrez] PHST- 2015/11/19 06:00 [pubmed] PHST- 2016/08/17 06:00 [medline] PHST- 2015/11/17 00:00 [pmc-release] AID - mBio.01298-15 [pii] AID - mBio01298-15 [pii] AID - 10.1128/mBio.01298-15 [doi] PST - epublish SO - mBio. 2015 Nov 17;6(6):e01298-15. doi: 10.1128/mBio.01298-15.