title: Treatment and prevention of urinary tract infection with orally active FimH inhibitors.
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.
authors.affiliation: Department of Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Corinne K
authors.initials: CK
authors.lastname: Cusumano
authors.forename: Jerome S
authors.initials: JS
authors.lastname: Pinkner
authors.forename: Zhenfu
authors.initials: Z
authors.lastname: Han
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Greene
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Ford
authors.forename: Jan R
authors.initials: JR
authors.lastname: Crowley
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Henderson
authors.forename: James W
authors.initials: JW
authors.lastname: Janetka
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
mesh_terms: D018830:Adhesins, Escherichia coli; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008362:Mannosides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D018613:Microscopy, Confocal; D015394:Molecular Structure; D014552:Urinary Tract Infections / Q000188:drug therapy*; D056689:Uropathogenic Escherichia coli / Q000187:drug effects / Q000472:pathogenicity*
chemical_list: D018830:Adhesins, Escherichia coli; D000900:Anti-Bacterial Agents; D008362:Mannosides; C058769:fimH protein, E coli; D036781:Fimbriae Proteins
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