Discovery of daspyromycins A and B, 2-aminovinyl-cysteine containing lanthipeptides, through a genomics-based approach

Lanthipeptides are one of the largest groups of ribosomally synthesized and post-translationally modified peptides (RiPPs) and are characterized by the presence of lanthionine (Lan) or methyllanthionine residues (MeLan). Only very few lanthipeptides contain a C-terminal 2-aminovinyl-cysteine (AviCys) motif, but all of them show potent antibacterial activities. Recent advances of genome sequencing led to the rapid accumulation of new biosynthetic gene clusters (BGCs) for lanthipeptides. In this study, through our genome mining strategy, we found the AviCys containing lanthipeptides are widespread in the bacterial kingdom. A lanthipeptide-type biosynthetic gene cluster was identified from public bacterial genome database. Two new lanthipeptides, daspyromycins A and B (1 and 2) containing AviCys motif, along with two degraded products, daspyromycins C and D (3 and 4), were obtained after heterologous expression of the gene cluster in Streptomyces albus J1074. Daspyromycins A and B showed potent antimicrobial activity against a spectrum of Gram-positive and -negative bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Two new 2-aminovinyl-cysteine (AviCys)-containing lanthipeptides were discovered and characterized through survey of 25,802 bacterial genomes. Both compounds exhibit potent antibacterial activities against a spectrum of bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). [Display omitted]