|
|||||
|
|
Heptyl α‐D‐Mannosides Grafted on a β‐Cyclodextrin Core To Interfere with Escherichia coli Adhesion: An In Vivo Multivalent Effect |
|
| Authors: | Dr Julie Bouckaert Dr Zhaoli Li Dr Catarina Xavier Dr Mehdi Almant Dr Vicky Caveliers Prof Tony Lahoutte Dr Stephen D Weeks Prof José Kovensky Dr Sébastien G Gouin |
| Institution: | 1. Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), UMR8576 du CNRS, Université Lille 1, F‐59655 Villeneuve d'Ascq Cedex (France), Fax: (+33)?320436555;2. Viral Genetics Research Group, Faculty of Science and Bio‐engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels (Belgium);3. In Vivo Cellular and Molecular Imaging (ICMI) Laboratory, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium);4. Laboratoire des Glucides FRE 3517, Institut de Chimie de Picardie, Faculté des Sciences, Université de Picardie Jules Verne, 33 rue Saint‐Leu, 80039 Amiens Cedex 1 (France);5. Laboratory for Biocrystallography, KU Leuven, Department of Pharmaceutical Sciences, O&N II Herestraat 49 – bus 822, 3000 Leuven (Belgium);6. Present address: 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), Fax: (+33)?276645175 |
| 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. |
| Keywords: | antibacterial agents biological activity click chemistry cyclodextrins glycoconjugates inhibitors |