Biochemical and structural study of the interaction of carbohydrate-based inhibitors with the FimH adhesin

Abstract

Urinary tract infections (UTIs) are among the most common bacterial infections. The majority of these infections are caused by uropathogenic E. coli (UPEC). Bacterial infections can be treated by the administration of antibiotics, but multi-drug resistant strains have emerged, which have highlighted the need of effective alternative therapeutic approaches.
UPEC express type 1 pili on their bacterial surface, which contain a FimH adhesin to adhere, colonize and invade bladder cells, consequently causing a UTI. The bacterial attachment of UPEC to the bladder can be hindered by anti-adhesive compounds that act as competitive inhibitors for the FimH - receptor interaction. Hence, knowledge of the interaction profile of this initial pathogen-host contact is highly important to provide insides in the pathogenic mechanism and in the development of antivirulence drugs, which could serve as curing and/or long-term prophylactic agents for UTIs.
Therefore, in this study, we unravelled the molecular interactions between FimH and its minimal receptor epitope by X-ray crystallography. Based on the obtained structural data, new soluble receptor analogues were rationally designed and screened on their capacity to disarm UPEC by targeting their type 1 pili-mediated cell adhesion. The structure-activity relationships obtained in this study are of high relevance for the further exploitation of anti-adhesive drugs, which can improve the lives of millions of people each year who suffer from this persistent and aggravating infectious disease.

Date of Award	18 Mar 2011
Original language	English
Supervisor	Henri De Greve (Promotor), Han Karel Remaut (Co-promotor), Julie Bouckaert (Co-promotor), Daniel Charlier (Jury), Jean-Pierre Hernalsteens (Jury), Serge Muyldermans (Jury), Stefan Oscarson (Jury) & S. Knight (Jury)