Overexpression of div8 increases the production and diversity of divergolides in Streptomyces sp. W112

Isolation and structure elucidation of divergolides from Streptomyces sp. HKI0576 revealed unusual ansamycin diversification reactions and the biosynthetic flexibility of the divergolide family. The production of divergolide E in Streptomyces sp. W112 was previously increased by overexpression of div8, which belongs to ATP-binding regulators of the LuxR family. In this study, we have further characterized the products of the div8-overexpressed mutant and five new divergolide congeners (1-5) were elucidated. Among them, 1-3 features conserved divergolide A skeleton, and 4 and 5 are lactone isomers and seco variant of divergolides E and D, respectively. Divergolides O-S (1-5) showed almost no toxicity to tested human cancer cell lines of MDA-MB-231, PC3 and HeLa at 50 mu M. Whereas, 4 and 5 significantly inhibited the secretion of SPI-1 effectors.