RATIONAL DESIGN OF MANNOSIDES FOR INHIBITION OF FIMH AND TREATMENT OF UTI

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DESCRIPTION (provided by applicant): The urinary tract (UT) is a common site of infection in humans, with an estimated 8 million outpatient visits in the U.S. and an estimated cost exceeding $2.5 billion annually. The most frequent sufferers are women, with a 50% lifetime chance of developing an acute UT infection (UTI), the majority caused by uropathogenic Escherichia coli (UPEC). Recurrence is a common problem. Women who present with an initial episode of acute UTI have a 25-44% chance of developing a second and a 3% chance of experiencing three episodes within six months. Due to considerable morbidity caused by this infection, the high recurrence rate and the rising incidence of bacterial antibiotic resistance, new strategies for treatment are necessary. UPEC produce type 1 pili that contain the mannose binding FimH tip adhesin. In the bladder, FimH mediates bacterial invasion into superficial facet cells. Inside these cells, UPEC rapidly replicate forming biofilm-like intracellular bacterial communities (IBCs). Upon dispersal of the IBC, UPEC spread to neighboring cells and repeat the cycle thus explaining how single bacteria are able to rapidly expand and gain a foothold and cause disease in the UT. One outcome of the acute IBC cascade is the formation of quiescent intracellular reservoirs (QIRs) that are not cleared by antibiotic treatments, can persist for months, and can seed new rounds of infection. We have determined the structural basis of the FimH-mannose interaction and the mechanism of pilus assembly. This knowledge forms the basis for rational design of compounds that block bacterial colonization, IBC formation and infection, by interfering with critical host-pathogen interactions. Funding of this proposal in response to challenge grant 15-DK-103 will greatly enhance our efforts to find alternative strategies for treatment of UTI which is critical in the face of rising antibiotic resistance and recurrence. Using rational structure-based drug design and synthesis, we propose to develop high affinity mannose derivatives (mannosides) that function to block disease by preventing bacterial expansion in the IBC cascade. We also have designed and produced pilicides that block pilus assembly. The drug-like properties including pharmokinetics, bioavailability and potential toxicity of the best inhibitors will be evaluated and their efficacy in blocking virulence will be assessed in a multitude of in vitro assays and in our in vivo murine model. PUBLIC HEALTH RELEVANCE: This grant to rationally design, synthesize and test the efficacy of type 1 pilus FimH adhesin inhibitors will greatly enhance our efforts to find alternative strategies for treatment of urinary tract infections, one of the most common infections in humans. This is particularly important due to rising antibiotic resistance and high UTI recurrence rates in otherwise healthy females.