Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease

Laurel K. Mydock-McGrane, Thomas J. Hannan, James W. Janetka

Research output: Contribution to journalReview article

21 Scopus citations

Abstract

Introduction: The bacterial adhesin FimH is a virulence factor and an attractive therapeutic target for urinary tract infection (UTI) and Crohn’s Disease (CD). Located on type 1 pili of uropathogenic E. coli (UPEC), the FimH adhesin plays an integral role in the pathogenesis of UPEC. Recent efforts have culminated in the development of small-molecule mannoside FimH antagonists that target the mannose-binding lectin domain of FimH, inhibiting its function and preventing UPEC from binding mannosylated host cells in the bladder, thereby circumventing infection. Areas covered: The authors describe the structure-guided design of mannoside ligands, and review the structural biology of the FimH lectin domain. Additionally, they discuss the lead optimization of mannosides for therapeutic application in UTI and CD, and describe various assays used to measure mannoside potency in vitro and mouse models used to determine efficacy in vivo. Expert opinion: To date, mannoside optimization has led to a diverse set of small-molecule FimH antagonists with oral bioavailability. With clinical trials already initiated in CD and on the horizon for UTI, it is the authors, opinion that mannosides will be a ‘first-in-class’ treatment strategy for UTI and CD, and will pave the way for treatment of other Gram-negative bacterial infections.

Original languageEnglish
Pages (from-to)711-731
Number of pages21
JournalExpert Opinion on Drug Discovery
Volume12
Issue number7
DOIs
StatePublished - Jul 3 2017

Keywords

  • AIEC
  • Crohn’s disease
  • FimH
  • UPEC
  • UTI
  • bacterial adhesin
  • lectin
  • mannoside
  • pili
  • structure-based drug design (SBDD)

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