Biotechnology and Bioengineering, Vol.118, No.6, 2243-2254, 2021
Genome mining of Streptomyces sp. CB00271 as a natural high-producer of beta-rubromycin and the resulting discovery of beta-rubromycin acid
beta-rubromycin (beta-RUB) (1) is an efficient inhibitor of human telomerase possessing a unique spiroketal moiety as a potential pharmacophore and regarded as a promising anticancer drug lead. But the development of (beta-RUB) (1) has long been hampered by its low titer and very poor water solubility. By adopting a genome mining strategy, an FAD-dependent monooxygenase RubN involving with the formation of the spiro system was applied as the probe and Streptomyces sp. CB00271 was screened out from our strain collection as an alternative natural high producer of beta-RUB (1). After a series of fermentation optimizations, CB00271 could produce 124.8 +/- 3.4 mg/L beta-RUB (1), which was the highest titer up to now. Moreover, the enhanced production of beta-RUB (1) in fermentation broth also led to the discovery of a new congener beta-RUB acid (7), which was structurally elucidated as the acid form of beta-RUB (1). Comparing to beta-RUB (1), the substituted carboxyl group endowed beta-RUB acid (7) much better solubility in serum and resulted in its higher activity towards tumor cells. Our work set up a solid base for the pilot-scale production of beta-RUB (1) and its congeners to facilitate their future development as promising anticancer drug leads, and also provide an alternative and practical strategy for the exploitation of other important microbial natural products.