Characterization of the Aminosugar Biosynthetic and Regulatory Genes of Vicenistatin in Monodonata labio -Associated Streptomyces parvus SCSIO Mla-L010.

Vicenistatin ( 1 ) is a potent polyketide antitumor antibiotic composed of a 20-membered macrolactam core appended to a unique aminosugar, vicenisamine. In this study, vicenistatin was isolated and its biosynthetic gene cluster identified from Monodonata labio -associated Streptomyces parvus SCSIO Mla-L010. A set of five genes, vicC , vicD , vicE , vicF , and vicG , was confirmed to be involved in the biosynthesis of the aminosugar by gene inactivations. VicG was characterized as an N -methyltransferase that catalyzes the methylation of the 4'-amino group in the last step of the aminosugar biosynthetic pathway; the N -demethyl intermediate 4'- N -demethylvicenistatin ( 2 ) was isolated from the Δ vicG mutant strain. In addition, vicR1 was characterized as a positive pathway-specific regulatory gene. Notably, N -demethyl compound 2 was found to exert impressive antibacterial activities, with MIC values spanning 0.06-4 μg/mL, against a panel of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus , Gram-negative Helicobacter pylori , and mycobacterium Mycobacterium smegmatis and the fungal pathogen Candida albicans . Compound 2 was also found to display reduced cytotoxicities relative to vicenistatin, especially against noncancerous human cell lines.