4-Aryl-2-aminoimidazole analogues of bromoageliferin with antimicrobial activity against Acinetobacter baumannii show in vitro inhibition of translocase MraY on the peptidoglycan biosynthesis pathway

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 ϕX174 to target translocase MraY on the peptidoglycan biosynthesis pathway. The analogues showed antimicrobial activity against a panel of ESKAPE pathogens, with compound 9c (substituent CF 3 ) showing effective antimicrobial activity against antibiotic-resistant Acinetobacter baumannii 19,606 (MIC 8 μg/mL) and Staphylococcus aureus MRSA USA300 (MIC 8 μg/mL). The analogues showed 33–47% inhibition of particulate E. coli MraY at 200 μM concentration, with highest enzyme inhibition shown by compound 9b (substituent F, IC 50 210 μM). Docking against the structure of E. coli MraY revealed a possible binding site in the “elbow” 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. • 4-Aryl-2-imidazoles were designed as new peptidomimetics for MraY inhibition. • 9c showed MIC 8 μg/mL against Acinetobacter baumannii 19,606. • Compounds showed 33–47% inhibition of E. coli MraY at 200 μM concentration. • Docking revealed a possible binding site in the “elbow” of bent helix 9.