Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections

Laurel Mydock-McGrane, Zachary Cusumano, Zhenfu Han, Jana Binkley, Maria Kostakioti, Thomas Hannan, Jerome S. Pinkner, Roger Klein, Vasilios Kalas, Jan Crowley, Nigam P. Rath, Scott J. Hultgren, James W. Janetka

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.

Original languageEnglish
Pages (from-to)9390-9408
Number of pages19
JournalJournal of Medicinal Chemistry
Volume59
Issue number20
DOIs
StatePublished - Oct 27 2016

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