Treatment and Prevention of Urinary Tract Infection with Orally Active FimH Inhibitors

Optimized mannoside compounds that block uropathogenic E. coli entry into bladder epithelium were effective in the treatment and prevention of urinary tract infections in mice. Bypassing Resistance to Treatment of Urinary Tract Infections Sometimes, we can have too much of a good thing. The antibiotics that allow us to survive microbial infections and save untold human lives brought with them the emergence of microbes resistant to these drugs. These resistant pathogens often make trouble in the urinary system, causing recurrent urinary tract infections (UTIs) in women that require long-term antibiotic use and resist treatment. To thwart the evolution of the drug-resistant Escherichia coli that favor the urinary tract, Cusumano et al. have developed a series of mannoside compounds as alternative antimicrobial drugs. Because these agents interfere with the ability of uropathogenic E. coli to bind to bladder epithelial cells through a receptor called FimH, they interrupt the E. coli life cycle, curing infection. Optimization of other features, including oral availability, yields a promising contender for translation into patients. From a panel of mannoside compounds, the authors selected one (termed 6) that inhibited E. coli biofilm production in culture at a relatively low dose and survived passage through the gut, allowing administration in pill form. When they gave it to mice with chronic UTIs, 6 quickly cause a drop in the bacteria in the bladder to a level considerably lower than that produced by the standard antibiotic treatment. And when mice received 6 before exposure to bacteria, they remained healthy, likely because the drug blocked bacterial entry into bladder cells. Compound 6’s ability to keep bacteria out of the epithelial cells of the bladder could also augment the action of the standard antibiotic by ensuring that the microbes stayed in the bladder lumen where they were exposed to maximal doses of antibiotics. In another round of chemical tweaking, the authors further improved compound 6 to increase its binding to FimH, cell permeability, oral bioavailability, and bladder tissue penetration. The result—compound 8—is an excellent lead candidate for the treatment and prevention of recurrent UTI. Safety and efficacy studies in women will test 8’s promise in bypassing the antibiotic resistance that complicates the management of this common infection. Chronic and recurrent urinary tract infections pose a serious medical problem because there are few effective treatment options. Patients with chronic urinary tract infections are commonly treated with long-term prophylactic antibiotics that promote the development of antibiotic-resistant forms of uropathogenic Escherichia coli (UPEC), further complicating treatment. We developed small–molecular weight compounds termed mannosides that specifically inhibit the FimH type 1 pilus lectin of UPEC, which mediates bacterial colonization, invasion, and formation of recalcitrant intracellular bacterial communities in the bladder epithelium. Here, we optimized these compounds for oral bioavailability and demonstrated their fast-acting efficacy in treating chronic urinary tract infections in a preclinical murine model. These compounds also prevented infection in vivo when given prophylactically and strongly potentiated the activity of the current standard of care therapy, trimethoprim-sulfamethoxazole, against clinically resistant PBC-1 UPEC bacteria. These compounds have therapeutic efficacy after oral administration for the treatment of established urinary tract infections in vivo. Their unique mechanism of action—targeting the pilus tip adhesin FimH—circumvents the conventional requirement for drug penetration of the outer membrane, minimizing the potential for the development of resistance. The small–molecular weight compounds described herein promise to provide substantial benefit to women suffering from chronic and recurrent urinary tract infections.