Optimization of Fermentation and Mutagenesis for Enhanced Staurosporine Production in the Marine-Derived Streptomyces Strain OUCMDZ-3118

Background: Staurosporine is a potent broad-spectrum alkaloid antibiotic originally isolated from Streptomyces sp. It is renowned for its strong inhibitory activity against protein kinases by competitively binding to their ATP-binding sites. Therefore, staurosporine and its derivatives have been extensively investigated for their potential as anticancer agents. However, a major challenge in its utilization is the low production yield in wild-type strains. To overcome this limitation, this study aimed to enhance staurosporine yield in marine-derived staurosporine-producing strain OUCMDZ-3118. Methods: The fermentation conditions were tested by single-factor experiment, Plackett–Burman experiment, steepest ascent path and Box–Benhnken response surface method. Subsequently, the ultraviolet mutagenesis was employed to generate high-yielding mutant strain. Results: The optimal culture conditions were 50 g/L rice, 50 g/L soybean powder, 3 g/L NaCl, 10 g/L L-tryptophan, inoculum concentration of 3% (v/v) in 150 mL of medium within a 500 mL flask, and fermentation time of 10 days. Following UV mutagenesis, the mutant strain produced a final staurosporine titer of 496 mg/L, an approximately 9.5-fold higher titer than that of the wild-type strain. In a 30-day solid-state fermentation under the conditions of 40 g rice, 40 g soybean powder, moistened with 80 mL water containing NaCl (3 g/L) and L-tryptophan (10 g/L), a yield of 578 mg per 80 g of substrate was also achieved. A consistent yield of 7.22 g/kg was achieved across approximately 1000 replicate fermentations under identical conditions, demonstrating the robustness of the process. Conclusions: This study yielded a stable, high-yielding strain for staurosporine production, paving the way for the development of staurosporine-based antitumor drugs and their derivatives.