Drug and Vaccine Development
While antibiotic therapy has been resoundingly successful in treating acute UTI, recent increases in the prevalence of resistance to first-line empiric therapies such as trimethoprim-sulfamethoxazole (TMP-SMZ) are leading to frequent use of fluoroquinolones as first line therapy for UTI. Further, multi-drug resistant strains threaten to make chronic/recurrent UTI an even more common problem. Thus, understanding the mechanisms contributing to acute UTI and progression to chronic and/or recurrent UTI is of critical clinical importance.
Our work has led to targeted development of therapeutic molecules, which block CUP pilus assembly or function. In collaboration with Jim Janetka, the FimH-mannose X-ray crystal structure was used to rationally design molecules, termed mannosides, which competitively inhibit FimH binding to its host receptor. These mannosides are potent inhibitors of biofilm formation in vitro and can prophylactically prevent acute UTI and treat chronic UTI in a mouse model when delivered orally.
In parallel, in collaboration with Dr. Fredrik Almqvist’s group, we have developed novel inhibitors of pili biogenesis, called pilicides, which were shown to inhibit UPEC biofilm formation in vitro and decrease type 1 pilus formation. Finally, a FimH vaccine is also being developed in which anti-FimH antibodies block FimH function and opsonize UPEC for clearance.
Collaborators: Fredrik Almqvist, Jim Janetka, Sequoia Sciences.