糖心TV

Roisin Murphy, Julia A. Fairbairn, Becca W.A. Baileeves, Phillip J. Stansfeld, Timothy D.H. Bugg

A series of 4-aryl-2-imidazoles containing an ortho-substituted benzyl substituent were designed as a new peptidomimetic scaffold for an Arg-Trp-x-x-Trp motif used by lysis protein E from bacteriophage 蠒X174 to target translocase MraY on the peptidoglycan biosynthesis pathway. The analogues showed antimicrobial activity against a panel of ESKAPE pathogens, with compound 9c (substituent CF₃) showing effective antimicrobial activity against antibiotic-resistant Acinetobacter baumannii 19606 (MIC 8 渭g/mL) and Staphylococcus aureus MRSA USA300 (MIC 8 渭g/mL). The analogues showed 33–47% inhibition of particulate E. coli MraY at 200 渭M concentration, with highest enzyme inhibition shown by compound 9b (substituent F, IC₅₀ 210 渭M). Docking against the structure of E. coli MraY revealed a possible binding site in the 鈥渆lbow鈥� of bent helix 9, close to Phe-288. This work identifies the MraY-protein E interaction site as a possible target for the antimicrobial activity of bromoageliferin, and establishes a new skeleton for design of non-nucleoside MraY inhibitors.