Uropathogenic Escherichia coli (UPEC) is the predominant causing agent of urinary tract infections (UTIs). A significant number of urinary tract infections in women treated with antibiotics and due to the resistance of antibiotics, treatment UTIs has becomes a serious global clinical challenge and the importance of alternative therapeutic development must be needed. UPEC strains have notable virulence factors that allow entry and establishment in the human host results the UTIs. Among the all UPEC express CUP pili, the F9/Yde/Fml pilus called Fml adhesion called FmlH to bind Gal-β1-3-GalNAc (Tf) epitope-containing bladder epithelial receptors, induced upon inflammation during chronic, unresolved UTI. We rationally designed the small-molecule aryl galactosides that specifically bind and inhibit the function of the FmlH (lectin). A combination of structure-guided design, virtual screening, and the ELISA-based assay led to the discovery of lead candidate. Using the X-ray structure of FmlH and virtual screening, new FmlH ligands, including O-nitro phenyl-β-galactoside (ONPG) were identified. Subsequently, the X-ray structures of Galβ-1-3-GalNAc (Tf) epitope and ONPG bound to FmlH reveals the further design of FmlH ligands and in which the β-GalNAc-biaryl analogs provided binding affinities in multiple folds higher than ONPG, as determined by an ELISA binding assay. This structure-guided design, synthesis and biological evaluation of β-GalNAc-biaryl analogs provided promising and further studies.

Aryl galactosides targeting FmlH antagonists for the treatment of urinary tract infections (UTIs)

255th National Meeting (2018)

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