Optimizing anti-virulence compounds for the treatment of UTIs

Washington University, Saint Louis MO

Investigators

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Abstract

DESCRIPTION (provided by applicant): Urinary tract infections are extremely common infections, affecting 50% of women in their lifetime, with many of these women experiencing recurrent infections. 80% of community acquired UTIs and 50% of nosocolial UTIs are caused by uropathogenic E. coli (UPEC). The increasing rates of antibiotic resistance in UPEC necessitate the development of novel therapeutics to treat these infections. UPEC uses the adhesive extracellular organelle type 1 pili to bind to mannose on the bladder epithelium, allowing the bacteria to attach and invade host cells and establish infection. In addition to type 1 pili, UPEC encode many homologous types of pili, including P and S pili, which are both also associated with UTIs. As our lab has elucidated the details of pilus assembly for these homologous types of pili, we were able to develop small molecules, rationally designed to disrupt pilus assembly. These anti-virulence compounds, termed pilicides, provide a novel approach for the treatment of UTIs, as preventing pilus assembly or function should lessen the virulence of UPEC, or other gram-negative pathogens encoding homologous pili. Therefore, we propose to study the efficacy of pilicides in disrupting assembly of all homologous pili in the UPEC strain UTI89, as well as in other uropathogens. Because these pili are often coordinately regulated, we will also examine the effects of pilicide on the expression of these pili. Furthermore, as pilus expression is affected by environmental signals, we will assess the expression of these pili and the function of pilicides in host-like environments, such as after growth in urine or attachment to human ureter tissue. We also have evidence that pilicides have other effects on UPEC in addition to disrupted pilus assembly. Using microarrays, we will elucidate these pilicide effects, such that we can understand all mechanisms of pilicide action. These studies will increase our understanding of pilicide effects on UPEC pili and allow us to further optimize these compounds for therapeutic use in treating UTIs.