Journal article
Treatment and prevention of urinary tract infection with orally active FimH inhibitors
Science translational medicine, Vol.3(109), pp.109ra115-ra115
11/16/2011
DOI: 10.1126/scitranslmed.3003021
PMCID: PMC3694776
PMID: 22089451
Abstract
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.
Details
- Title: Subtitle
- Treatment and prevention of urinary tract infection with orally active FimH inhibitors
- Creators
- Corinne K Cusumano - Department of Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USAJerome S PinknerZhenfu HanSarah E GreeneBradley A FordJan R CrowleyJeffrey P HendersonJames W JanetkaScott J Hultgren
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.3(109), pp.109ra115-ra115
- DOI
- 10.1126/scitranslmed.3003021
- PMID
- 22089451
- PMCID
- PMC3694776
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Publisher
- United States
- Grant note
- P30-DK56341 / NIDDK NIH HHS P60 DK020579 / NIDDK NIH HHS RC1 DK086378 / NIDDK NIH HHS AI48689 / NIAID NIH HHS R01 DK051406 / NIDDK NIH HHS P41-RR00954 / NCRR NIH HHS DK51406 / NIDDK NIH HHS P41 RR000954 / NCRR NIH HHS P50 DK064540 / NIDDK NIH HHS AI49950 / NIAID NIH HHS RC1DK086378-02 / NIDDK NIH HHS P60-DK20579 / NIDDK NIH HHS R01 AI048689 / NIAID NIH HHS K12 HD001459 / NICHD NIH HHS P30 DK056341 / NIDDK NIH HHS DK64540 / NIDDK NIH HHS K12 HD001459-09 / NICHD NIH HHS R01 AI049950 / NIAID NIH HHS
- Language
- English
- Date published
- 11/16/2011
- Academic Unit
- Pathology
- Record Identifier
- 9984047854202771
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