Multivalent calix[4]arene-based mannosylated dendrons as new FimH ligands and inhibitors

We report the synthesis and biological characterization of a novel class of multivalent glycoconjugates as hit compounds for the design of new antiadhesive therapies against urogenital tract infections (UTIs) caused by uropathogenic E. coli strains (UPEC). The first step of UTIs is the molecular recognition of high mannose N-glycan expressed on the surface of urothelial cells by the bacterial lectin FimH, allowing the pathogen adhesion required for mammalian cell invasion. The inhibition of FimH-mediated interactions is thus a validated strategy for the treatment of UTIs. To this purpose, we designed and synthesized D-mannose multivalent dendrons supported on a calixarene core introducing a significant structural change from a previously described family of dendrimers bearing the same dendrons units on a flexible pentaerythritol scaffold core. The new molecular architecture increased the inhibitory potency against FimH-mediated adhesion processes by about 16 times, as assessed by yeast agglutination assay. Moreover, the direct molecular interaction of the new compounds with FimH protein was assessed by oncell NMR experiments acquired in the presence of UPEC cells.

Automated summary

We synthesized a new class of multivalent glycoconjugates for the treatment of UTIs caused by UPEC. These compounds showed increased inhibitory potency against FimH-mediated adhesion processes compared to previous dendrimers, as demonstrated by yeast agglutination assay. Furthermore, the direct molecular interaction between the compounds and FimH protein was confirmed by on-cell NMR experiments.