Does targeting Arg98 of FimH lead to high affinity antagonists?

Bacterial resistance has become an important challenge in the treatment of urinary tract infections. The underlying mechanisms can most likely be circumvented with antiadhesive approach, antagonizing lectin FimH located at tip fimbriae uropathogenic E. coli. Here we report on a novel series antagonists based 1-(?-d-mannopyranosyl)-4-phenyl-1,2,3-triazole scaffold, designed to incorporate carboxylic acid or ester functions interact Arg98. potent representative series, 11e, displayed Kd value 7.6 nM for domain general conclusion that all esters outperform carboxylates terms affinity. Surprisingly, compounds from this new exhibited improved binding affinities also R98A mutant, indicating another possible interaction contributing binding. Our study 1-(?-d-mannopyranosyl)-4-phenyl-1,2,3-triazole-based offers proof targeting Arg98 side chain by “chemical common sense”, i.e. introduction acidic moiety form ionic bond is unsuitable approach boost antagonists’ potency.