Enhancing Borrelidin Biosynthesis in an Indonesian Endophytic <i>Streptomyces</i> sp. via Medium Optimization for Potential Pharmaceutical Application

Borrelidin is a pharmacologically active 18-membered macrolide with antibacterial, antifungal, anticancer, and antimalarial activities; however, its pharmaceutical development has been constrained by low fermentation yields. In this study, borrelidin production by an endophytic Streptomyces sp. isolated from the medicinal plant Zingiber zerumbet (L.) Smith was significantly enhanced through systematic medium optimization. A high-producing colony (BR7) was selected, and key nutritional variables were optimized using response surface methodology based on a Box–Behnken design (BBD). Statistical analysis revealed that borrelidin biosynthesis is governed primarily by strong quadratic and interaction effects among carbon and nitrogen sources rather than by individual nutrients. The optimized agro-based medium increased borrelidin concentration to approximately 83 mg/L, in close agreement with model predictions and representing a substantial improvement over the unoptimized process. The use of low-cost agricultural substrates supports the scalability and economic feasibility of this fermentation strategy. Overall, this work establishes a robust upstream bioprocess framework that supports the pharmaceutical development of borrelidin as a potential active pharmaceutical ingredient (API).