title: The Antiadhesive Strategy in Crohn's Disease: Orally Active Mannosides to Decolonize Pathogenic Escherichia coli from the Gut.
abstract: Blocking the adherence of bacteria to cells is an attractive complementary approach to current antibiotic treatments, which are faced with increasing resistance. This strategy has been particularly studied in the context of urinary tract infections (UTIs), in which the adhesion of pathogenic Escherichia coli strains to uroepithelial cells is prevented by blocking the FimH adhesin expressed at the tips of bacteria organelles called fimbriae. Recently, we extended the antiadhesive concept, showing that potent FimH antagonists can block the attachment of adherent-invasive E. coli (AIEC) colonizing the intestinal mucosa of patients with Crohn's disease (CD). In this work, we designed a small library of analogues of heptyl mannoside (HM), a previously identified nanomolar FimH inhibitor, but one that displays poor antiadhesive effects in vivo. The anomeric oxygen atom was replaced by a sulfur or a methylene group to prevent hydrolysis by intestinal glycosidases, and chemical groups were attached at the end of the alkyl tail. Importantly, a lead compound was shown to reduce AIEC levels in the feces and in the colonic and ileal mucosa after oral administration (10 mg kg(-1) ) in a transgenic mouse model of CD. The compound showed a low bioavailability, preferable in this instance, thus suggesting the possibility of setting up an innovative antiadhesive therapy, based on the water-soluble and non-cytotoxic FimH antagonists developed here, for the CD subpopulation in which AIEC plays a key role.
authors.affiliation: LUNAM Université, CEISAM, Chimie et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, 2, rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Alvarez Dorta
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, 63000, Clermont-Ferrand, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Sivignon
authors.affiliation: LUNAM Université, CEISAM, Chimie et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, 2, rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Chalopin
authors.affiliation: Univ. Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France.
authors.forename: Tetiana I
authors.initials: TI
authors.lastname: Dumych
authors.affiliation: Structure and Function of Biological Membranes, Université Libre de Bruxelles, Boulevard du Triomphe, 1050, Brussels, Belgium.
authors.forename: Goedele
authors.initials: G
authors.lastname: Roos
authors.affiliation: Danylo Halytsky Lviv National Medical University, Pekarska Str. 69, 79010, Lviv, Ukraine.
authors.forename: Rostyslav O
authors.initials: RO
authors.lastname: Bilyy
authors.affiliation: LUNAM Université, CEISAM, Chimie et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, 2, rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
authors.forename: David
authors.initials: D
authors.lastname: Deniaud
authors.affiliation: Univ. Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Krammer
authors.affiliation: Univ. Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: de Ruyck
authors.affiliation: Univ. Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France.
authors.forename: Marc F
authors.initials: MF
authors.lastname: Lensink
authors.affiliation: Univ. Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Bouckaert
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, 63000, Clermont-Ferrand, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barnich
authors.affiliation: LUNAM Université, CEISAM, Chimie et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, 2, rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France. sebastien.gouin@univ-nantes.fr.
authors.forename: Sébastien G
authors.initials: SG
authors.lastname: Gouin
mesh_terms: D018830:Adhesins, Escherichia coli / Q000378:metabolism; D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects*; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003424:Crohn Disease / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000187:drug effects*; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000382:microbiology*; D008362:Mannosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D000072417:Protein Domains
chemical_list: D018830:Adhesins, Escherichia coli; D008362:Mannosides; C058769:fimH protein, E coli; D036781:Fimbriae Proteins
keywords: Crohn′s disease; FimH; cell adhesion; inhibitors; lectins; mannosides