Target Selectivity of FimH Antagonists

J Med Chem. 2012 Nov 26;55(22):9810-6. doi: 10.1021/jm3010338. Epub 2012 Nov 1.

Abstract

Mannose-based FimH antagonists are considered new therapeutics for the treatment of urinary tract infections (UTIs). They prevent the adhesion of uropathogenic Escherichia coli (UPEC) to urothelial cell surfaces triggered by the lectin FimH, which is located at the tip of bacterial type 1 pili. Because all reported FimH antagonists are α-d-mannosides, they are also potential ligands of mannose receptors of the human host system. We therefore investigated the selectivity range of five FimH antagonists belonging to different compound families by comparing their affinities for FimH and eight human mannose receptors. On the basis of the detected selectivity range of approximately 5 orders of magnitude, no adverse side effects resulting from nonselective binding to the human receptors have to be expected. FimH antagonists can therefore be further considered as potential therapeutics for the treatment of UTI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adhesins, Escherichia coli / drug effects*
  • Fimbriae Proteins / antagonists & inhibitors*
  • Host-Pathogen Interactions / drug effects*
  • Humans
  • Lectins, C-Type / metabolism
  • Mannose / metabolism*
  • Mannose Receptor
  • Mannose-Binding Lectins / metabolism
  • Mannosides / pharmacology*
  • Molecular Structure
  • Myelin Basic Protein / metabolism
  • Receptors, Cell Surface / metabolism
  • Structure-Activity Relationship
  • Urinary Tract Infections / drug therapy*
  • Uropathogenic Escherichia coli / drug effects*

Substances

  • Adhesins, Escherichia coli
  • Lectins, C-Type
  • MBP protein, human
  • Mannose Receptor
  • Mannose-Binding Lectins
  • Mannosides
  • Myelin Basic Protein
  • Receptors, Cell Surface
  • fimH protein, E coli
  • Fimbriae Proteins
  • Mannose