Antimicrobial resistance is a critical global health threat. This paper reports the discovery of new aminovinyl-(methyl)cysteine (Avi(Me)Cys)-containing peptide antibiotics using a combined bioinformatic and experimental approach. Bioinformatic analysis of over 50,000 bacterial genomes identified 1172 biosynthetic gene clusters (BGCs) for Avi(Me)Cys-containing peptides. Three BGCs were linked to the biosynthesis of five peptide antibiotics, including massatide A, a class V lanthipeptide with potent activity against drug-resistant Gram-positive pathogens. Massatide A demonstrated efficacy in an animal infection model with a low resistance risk and favorable safety profile, making it a promising antibiotic candidate.
