Natural Product Biosynthesis by Streptomyces venezuelae: Genetic Variants for Drug Discovery

Abstract

Natural product biosynthesis in Streptomyces venezuelae ISP5230 was investigated in three ways. First, through precursor-directed jadomycin biosynthesis using non-proteinogenic amino acids (4-(aminomethyl)benzoic acid, 3-(aminomethyl)benzoic acid, 8-aminooctanoic acid), five novel jadomycins were isolated and characterized. Four novel jadomycins were evaluated for cytotoxic activity in drug-sensitive and drug-resistant cancer cells and a panel of six microbes. Next, jadomycin C-glycoside production was attempted by heterologous expression of urdGT2 in place of the native O-glycosyltransferase, jadS. C-glycoside production was not observed from three complementation methods pursued. Finally, a S. venezuelae mutant was prepared to evaluate a silent biosynthetic gene cluster identified through genome mining. While the changes to the biosynthetic profile were apparent in the activator overexpression mutant, the major products detected were previously identified metabolites of tryptophan, including tryptophol. The studies demonstrated the pliability of S. venezuelae ISP5230 as a producer of natural products through manipulations to growth conditions, supplementation, and genetic variation.