Antarmycins: Discovery, Biosynthesis, Anti-pathogenic Bacterial Activity, and Mechanism of Action from Deep-Sea-Derived .

The rapid emergence of antimicrobial-resistant pathogenic microbes has accelerated the search for novel therapeutic agents. Here we report the discovery of antarmycin A (), an antibiotic containing a symmetric 16-membered macrodiolide core with two pendant vancosamine moieties, one of which is glucosylated, from deep-sea-derived SCSIO 07407. The biosynthetic gene cluster of was identified on a giant plasmid featuring transferable elements. In-depth biosynthetic investigation enabled us to (i) identify a set of seven genes associated with the product of the vancosamine moiety; (ii) discover two glycosyltransferases dedicated to the transfer of pendant sugars; and (iii) isolate rhamnose-modified antarmycin B () and a deglucosylated derivative antarmycin C () from genetically engineered mutant strains. Antibacterial assays revealed that displays superior antibacterial properties with potent activities against the critical priority pathogens, multidrug-resistant and methicillin-resistant , fast bacterial killing, insusceptibility to antimicrobial resistance, and high efficiency in infection models. Mechanistic investigations revealed that disrupts the bacterial cell membrane through a mechanism involving interactions between the vancosamine moieties and membrane-embedded phosphatidylglycerol/phosphatidylethanolamine. The results provide insights into the biological generation of vancosamine in natural products and demonstrate the potential of as an effective lead to address the growing antimicrobial resistance threats.