Synthesis and structure–activity study of the antimicrobial lipopeptide brevibacillin

Abstract

The antimicrobial lipopeptide brevibacillin is a non-ribosomally synthesized peptide produced by Brevibacillus laterosporus with inhibitory activity against several clinically relevant Gram-positive pathogenic bacteria such as Staphylococcus aureus, Listeria monocytogenes, and Clostridium difficile. In this study, we report the total synthesis of brevibacillin and analogues thereof as well as structure–activity relationship and cytotoxicity studies. Several novel synthetic analogues exhibited high inhibitory activities with minimal inhibitory concentration values in the low micromolar range against several bacteria including Gram-positive L. monocytogenes, S. aureus, Enterococcus faecalis, and Clostridium perfringens as well as Gram-negative Campylobacter coli and Pseudomonas aeruginosa. Of particular interest, four analogues showed a broad spectrum of action and greater antimicrobial activity versus cytotoxicity ratios than native brevibacillin. With a more accessible and efficient production process and improved pharmacological properties, these synthetic analogues are promising candidates to prevent and control the proliferation of various pathogens in the food industry as well as veterinary and human medicine.