Discovery of Six Ramoplanin Family Gene Clusters and the Lipoglycodepsipeptide Chersinamycin

Ramoplanins and enduracidins are peptidoglycan lipid intermediate II‐binding lipodepsipeptides with broad‐spectrum activity against methicillin‐ and vancomycin‐resistant Gram‐positive pathogens. Targeted genome mining using probes from conserved sequences within the ramoplanin/enduracidin biosynthetic gene clusters (BGCs) was used to identify six microorganisms with BGCs predicted to produce unique lipodepsipeptide congeners of ramoplanin and enduracidin. Fermentation of Micromonospora chersina yielded a novel lipoglycodepsipeptide, called chersinamycin, which exhibited good antibiotic activity against Gram‐positive bacteria (1–2 μg/mL) similar to the ramoplanins and enduracidins. The covalent structure of chersinamycin was determined by NMR spectroscopy and tandem mass spectrometry in conjunction with chemical degradation studies. These six new BGCs and isolation of a new antimicrobial peptide provide much‐needed tools to investigate the fundamental aspects of lipodepsipeptide biosynthesis and to facilitate efforts to produce novel antibiotics capable of combating antibiotic‐resistant infections. Genome mining has expanded the ramoplanin family of antibiotics with the identification of complete biosynthetic gene clusters in six new bacterial strains. The new antibiotic chersinamycin from M. chersina compares favorably with the antimicrobial activity of ramoplanin. The work described herein will provide new opportunities for investment in second‐generation analogues of this important peptide class.