TY  - JOUR
AU  - Bouckaert, Julie
AU  - Li, Zhaoli
AU  - Xavier, Catarina
AU  - Almant, Mehdi
AU  - Caveliers, Vicky
AU  - Lahoutte, Tony
AU  - Weeks, Stephen
AU  - Kovensky, José
AU  - Gouin, Sébastien G.
TI  - Heptyl α- D -Mannosides Grafted on a β-Cyclodextrin Core To Interfere with Escherichia coli Adhesion: An In Vivo Multivalent Effect
JO  - Chemistry
VL  - 19
IS  - 24
SN  - 0947-6539
CY  - Weinheim
PB  - Wiley-VCH
M1  - DESY-2014-02452
SP  - 7847 - 7855
PY  - 2013
N1  - © WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim
AB  - 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.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000319825500025
C6  - pmid:23595913
DO  - DOI:10.1002/chem.201204015
UR  - https://bib-pubdb1.desy.de/record/168260
ER  -