Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC): Optimization through Iterative Rational Drug Design

J Med Chem. 2019 Jan 24;62(2):467-479. doi: 10.1021/acs.jmedchem.8b01561. Epub 2019 Jan 2.


The F9/Yde/Fml pilus, tipped with the FmlH adhesin, has been shown to provide uropathogenic Escherichia coli (UPEC) a fitness advantage in urinary tract infections (UTIs). Here, we used X-ray structure guided design to optimize our previously described ortho-biphenyl Gal and GalNAc FmlH antagonists such as compound 1 by replacing the carboxylate with a sulfonamide as in 50. Other groups which can accept H-bonds were also tolerated. We pursued further modifications to the biphenyl aglycone resulting in significantly improved activity. Two of the most potent compounds, 86 (IC50 = 0.051 μM) and 90 (IC50 = 0.034 μM), exhibited excellent metabolic stability in mouse plasma and liver microsomes but showed only limited oral bioavailability (<1%) in rats. Compound 84 also showed a good pharmacokinetic (PK) profile in mice after IP dosing with compound exposure above the IC50 for 6 h. These new FmlH antagonists represent new antivirulence drugs for UTIs.

Publication types

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

MeSH terms

  • Adhesins, Escherichia coli / chemistry*
  • Adhesins, Escherichia coli / metabolism
  • Administration, Oral
  • Animals
  • Biphenyl Compounds / chemistry*
  • Drug Design*
  • Galactosamine / chemistry*
  • Galactosamine / pharmacokinetics
  • Galactosamine / therapeutic use
  • Galactose / chemistry*
  • Galactose / pharmacokinetics
  • Half-Life
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Rats
  • Structure-Activity Relationship
  • Urinary Tract Infections / drug therapy
  • Uropathogenic Escherichia coli


  • Adhesins, Escherichia coli
  • Biphenyl Compounds
  • FmlH protein, E coli
  • diphenyl
  • Galactosamine
  • Galactose