RT Journal Article
SR Electronic
T1 Treatment and Prevention of Urinary Tract Infection with Orally Active FimH Inhibitors
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 109ra115
OP 109ra115
DO 10.1126/scitranslmed.3003021
VO 3
IS 109
A1 Cusumano, Corinne K.
A1 Pinkner, Jerome S.
A1 Han, Zhenfu
A1 Greene, Sarah E.
A1 Ford, Bradley A.
A1 Crowley, Jan R.
A1 Henderson, Jeffrey P.
A1 Janetka, James W.
A1 Hultgren, Scott J.
YR 2011
UL http://stm.sciencemag.org/content/3/109/109ra115.abstract
AB 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.