Structure-Based Drug Design and Optimization of Mannoside Bacterial FimH Antagonists

TLDR

FimH-mediated adhesion to mannosylated proteins is essential for uropathogenic E. coli to colonize and invade bladder epithelium during urinary tract infection. The study reports the discovery and optimization of potent small‑molecule FimH antagonists based on α‑d‑mannose 1‑position anomeric glycosides using X‑ray structure‑guided drug design. X‑ray crystallography guided the design, revealing that the biphenyl moiety engages key FimH residues (Tyr‑48, Arg‑98/Glu‑50) through π‑π and electrostatic interactions.

Abstract

FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic E. coli (UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on α-d-mannose 1-position anomeric glycosides using X-ray structure-guided drug design. Optimized biarylmannosides display low nanomolar binding affinity for FimH in a fluorescence polarization assay and submicromolar cellular activity in a hemagglutination (HA) functional cell assay of bacterial adhesion. X-ray crystallography demonstrates that the biphenyl moiety makes several key interactions with the outer surface of FimH including π−π interactions with Tyr-48 and an H-bonding electrostatic interaction with the Arg-98/Glu-50 salt bridge. Dimeric analogues linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. The FimH antagonists described herein hold great potential for development as novel therapeutics for the effective treatment of urinary tract infections.