Improvement of Aglycone π‐Stacking Yields Nanomolar to Sub‐nanomolar FimH Antagonists

Abstract

Abstract Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti‐adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium‐affinity state in the absence and a high‐affinity state in the presence of shear forces. Until recently, mostly the high‐affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low‐affinity state. In this communication, we demonstrate that fluorination of biphenyl α‐ d ‐mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub‐nanomolar K D values for the low‐ and high‐affinity states, respectively. The face‐to‐face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as 1 H, 15 N‐HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.