Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI

ChemMedChem. 2016 Feb 17;11(4):367-73. doi: 10.1002/cmdc.201600006. Epub 2016 Jan 26.


Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo. In a rational design strategy, we obtained an X-ray structure of lead mannosides and then designed mannosides with improved drug-like properties. We show that cyclizing the carboxamide onto the biphenyl B-ring aglycone of biphenyl mannosides into a fused heterocyclic ring, generates new biaryl mannosides such as isoquinolone 22 (2-methyl-4-(1-oxo-1,2-dihydroisoquinolin-7-yl)phenyl α-d-mannopyranoside) with enhanced potency and in vivo efficacy resulting from increased oral bioavailability. N-Substitution of the isoquinolone aglycone with various functionalities produced a new potent subseries of FimH antagonists. All analogues of the subseries have higher FimH binding affinity than unsubstituted lead 22, as determined by thermal shift differential scanning fluorimetry assay. Mannosides with pyridyl substitution on the isoquinolone group inhibit bacteria-mediated hemagglutination and prevent biofilm formation by UPEC with single-digit nanomolar potency, which is unprecedented for any FimH antagonists or any other antivirulence compounds reported to date.

Keywords: FimH; biofilms; mannosides; urinary tract infections; uropathogenic E. coli.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adhesins, Escherichia coli / metabolism*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Chronic Disease
  • Escherichia coli Infections / drug therapy*
  • Escherichia coli Infections / microbiology
  • Fimbriae Proteins / metabolism*
  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Mannosides / chemistry
  • Mannosides / pharmacology*
  • Molecular Docking Simulation
  • Urinary Bladder / microbiology
  • Urinary Tract Infections / drug therapy*
  • Urinary Tract Infections / microbiology
  • Uropathogenic Escherichia coli / drug effects*
  • Uropathogenic Escherichia coli / metabolism


  • Adhesins, Escherichia coli
  • Anti-Bacterial Agents
  • Isoquinolines
  • Mannosides
  • fimH protein, E coli
  • Fimbriae Proteins