Engineering an Industrial Streptomyces albus Strain to Enable High-Yield Heterologous Production of Spectinabilin

Streptomyces species are major producers of bioactive molecules via biosynthetic gene clusters (BGCs). However, many BGCs are silent or poorly expressed in their native hosts, making heterologous expression hosts a key strategy for discovering novel natural products and efficiently producing known compounds. In this study, Streptomyces albus ZD11, an industrial salinomycin producer capable of efficiently utilizing soybean oil to supply abundant polyketide precursors, was selected as a candidate host for the expression of polyketide BGCs. A genome-reduced derivative, designated ZD12, was constructed by deleting four endogenous polyketide BGCs from ZD11, aiming to reduce precursor competition and alleviate metabolic burden. To evaluate the polyketide biosynthesis capacity of ZD12, an engineered spectinabilin BGC was heterologously expressed in both ZD12 and a commonly used heterologous host S. albus J1074. The resulting ZD12-derived strain DHM produced 412 mg/L spectinabilin, while the J1074-derived strain J-DHM produced 114 mg/L, both of which were significantly higher than the native production level in S. spectabilis. Notably, the titer in DHM exceeded the highest previously reported heterologous titer by more than threefold. Furthermore, under identical integration conditions, DHM achieved a 2.6-fold higher spectinabilin titer than J-DHM, demonstrating the superior polyketide biosynthesis capacity of ZD12.