title: Physiochemical Tuning of Potent Escherichia coli Anti-Adhesives by Microencapsulation and Methylene Homologation.
abstract: Thiazolylaminomannosides (TazMan) are FimH antagonists with anti-adhesive potential against adherent-invasive Escherichia coli (AIEC) promoting gut inflammation in patients with Crohn's disease. The lead TazMan is highly potent in vitro, but shows limited in vivo efficiency, probably due to low pH stability and water solubility. We recently developed a second generation of stable TazMan, but the anti-adhesive effect was lower than the first. Herein we report a co-crystal structure of the lead TazMan in FimH, revealing that the anomeric NH group and the second thiazole moiety provide a positive hydrogen bonding interaction with a trapped water molecule, and π-stacking with Tyr48 of FimH, respectively. Consequently, we developed NeoTazMan homologated with a methylene group for low-pH and mannosidase stability with a conserved NH group and bearing various heterocyclic aglycones. Microencapsulation of the lead NeoTazMan in γ-cyclodextrin dramatically improved water solubility without disrupting the affinity for FimH or the anti-adhesive effect against AIEC isolated from patients with Crohn's disease.
authors.affiliation: LUNAM Université, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Alvarez Dorta
authors.affiliation: LUNAM Université, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Chalopin
authors.affiliation: Université Clermont Auvergne, Inserm U1071, M2iSH, USC-INRA 2018, 63000, Clermont-Ferrand, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Sivignon
authors.affiliation: Université Lille, Unité de Glycobiologie Structurale et Fonctionnelle, CNRS UMR8576 UGSF, FRABio FR3688, 59000, Lille, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: de Ruyck
authors.affiliation: Danylo Halytsky Lviv National Medical University, Pekarska Str. 69, 79010, Lviv, Ukraine.
authors.forename: Tetiana I
authors.initials: TI
authors.lastname: Dumych
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, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
authors.forename: David
authors.initials: D
authors.lastname: Deniaud
authors.affiliation: Université Clermont Auvergne, Inserm U1071, M2iSH, USC-INRA 2018, 63000, Clermont-Ferrand, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barnich
authors.affiliation: Université Lille, Unité de Glycobiologie Structurale et Fonctionnelle, CNRS UMR8576 UGSF, FRABio FR3688, 59000, Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Bouckaert
authors.affiliation: LUNAM Université, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
authors.forename: Sébastien G
authors.initials: SG
authors.lastname: Gouin
mesh_terms: D018830:Adhesins, Escherichia coli; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001422:Bacterial Adhesion / Q000187:drug effects*; D002214:Capsules; D003424:Crohn Disease / Q000382:microbiology; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects*; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D018830:Adhesins, Escherichia coli; D000900:Anti-Bacterial Agents; D002214:Capsules; C058769:fimH protein, E coli; D036781:Fimbriae Proteins; D008697:Methane
keywords: C-mannosides; Crohn's disease; FimH antagonists; anti-adhesive therapy; microencapsulation