FimH antagonists and their therapeutic options in urinary tract infection : an example of an anti-adhesive therapy for infectious diseases

Abstract

FimH antagonists are small molecule inhibitors, derived from α-D-mannose, which block the adhesion of uropathogenic Escherichia coli (UPEC) to bladder cells. The abolition of binding leads to clearance of the bacteria with the urine flow and prevents urinary tract infections (UTIs). Within this thesis, the merits as well as problems of an anti-adhesive therapy (in the context of the infection cycle of UTI) as an alternative approach to combat bacterial infections are described. Previous reports showed successful applications of FimH antagonists in vitro and in vivo. The antagonists reduced bacterial attachment to cells and surfaces and decreased bladder infections in a UTI mouse model. Within this thesis, FimH antagonists from our group were screened for their minimal anti-adhesive concentration (MAC90) using an in vitro cell infection assay. The minimal therapeutic concentration was analyzed in the context of the pharmacokinetic (PK) performance of individual antagonists. It could be shown, that a preventive application and the resulting peak concentration of a FimH antagonist in the urine relative to the MAC90 value is predictive for positive treatment outcome. Guided by this finding, several treatment regimens, including combination therapies with antibiotics, were successfully applied to reduce bladder infections in an experimental mouse model by up to three orders of magnitude. Furthermore, FimH antagonists were effective against catheter-associated UTI (CAUTI), assessed by a newly established 96-well screening assay, using catheter pieces and human urine. They prevented biofilm formation in concentrations as low as 6.25 µg/ml. Moreover, in all tested applications, FimH antagonists exhibited a synergistic effect with ciprofloxacin (CIP), implying the possibility of combination therapies. Antagonizing the FimH lectin proofed cumbersome, because depending on the UPEC strain, the FimH binding pocket exhibits different affinity states towards mannose ligands. This leads to different MAC90 values for every individual strain and a specific antagonist. Besides, different strains vary in their infection course over longer time periods, probably related to the different affinity state of the FimH lectin. Consequently, the differences in affinity in combination with the infection time course might strongly influence treatment regimens, which will be an important topic of future investigations.