title: Heptyl α-D-mannosides grafted on a β-cyclodextrin core to interfere with Escherichia coli adhesion: an in vivo multivalent effect.
abstract: 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.
authors.affiliation: Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), UMR8576 du CNRS, Université Lille 1, F-59655 Villeneuve d'Ascq Cedex, France. julie.bouckaert@univ-lille1.fr
authors.forename: Julie
authors.initials: J
authors.lastname: Bouckaert
authors.forename: Zhaoli
authors.initials: Z
authors.lastname: Li
authors.forename: Catarina
authors.initials: C
authors.lastname: Xavier
authors.forename: Mehdi
authors.initials: M
authors.lastname: Almant
authors.forename: Vicky
authors.initials: V
authors.lastname: Caveliers
authors.forename: Tony
authors.initials: T
authors.lastname: Lahoutte
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weeks
authors.forename: José
authors.initials: J
authors.lastname: Kovensky
authors.forename: Sébastien G
authors.initials: SG
authors.lastname: Gouin
mesh_terms: D018830:Adhesins, Escherichia coli; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002151:Calorimetry; D057930:Click Chemistry; D004926:Escherichia coli / Q000737:chemistry / Q000187:drug effects*; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors*; D010861:Fimbriae, Bacterial / Q000187:drug effects; D008362:Mannosides / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018830:Adhesins, Escherichia coli; D000900:Anti-Bacterial Agents; D008362:Mannosides; D047392:beta-Cyclodextrins; C058769:fimH protein, E coli; D036781:Fimbriae Proteins; C031215:betadex