Work

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

Year: 2024

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide The rapid emergence of antimicrobial-resistant pathogenic microbes has accelerated the search for novel therapeutic agents. Here we report the discovery of antarmycin A ( 1 ), an antibiotic containing a symmetric 16-membered macrodiolide core with two pendant vancosamine moieties, one of which is glucosylated, from deep-sea-derived Pseudonocardia antarctica SCSIO 07407. The biosynthetic gene cluster of 1 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 ( 2 ) and a deglucosylated derivative antarmycin C ( 3 ) from genetically engineered mutant strains. Antibacterial assays revealed that 1 displays superior antibacterial properties with potent in vitro activities against the critical priority pathogens, multidrug-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus, fast bacterial killing, insusceptibility to antimicrobial resistance, and high in vivo efficiency in infection models. Mechanistic investigations revealed that 1 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 1 as an effective lead to address the growing antimicrobial resistance threats.

Source: JACS Au

DOI: 10.1021/jacsau.4c00912