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<p><i>Streptomyces</i> species are prolific producers of a diverse array of bioactive secondary metabolites (SMs), which constitute approximately two-thirds of natural product-based pharmaceuticals with significant clinical, agricultural, and biotechnological applications. However, the regulatory mechanisms underlying the biosynthesis of these compounds remain poorly understood, impeding the development of high-yielding strains for industrial production. Herein, we investigated the role of the WhiB-like (Wbl) family transcriptional regulator, WhiD<sub>sbh</sub>, in modulating SM production in <i>Streptomyces bingchenggensis</i> BC04. Overexpression of <i>whiD</i><sub><i>sbh</i></sub> in BC04 significantly suppressed milbemycin production by repressing the transcription of the milbemycin biosynthetic gene cluster via the ActK/R-KelR regulatory cascade. Comparative transcriptomic analysis between the <i>whiD</i><sub><i>sbh</i></sub> overexpression strain and BC04 revealed that <i>whiD</i><sub><i>sbh</i></sub> overexpression not only altered the expression of multiple other biosynthetic gene clusters but also impacted genes involved in central carbon metabolism, glutathione biosynthesis, and cofactor synthesis. Furthermore, cross-species genetic analysis demonstrated that <i>whiD</i><sub><i>sbh</i></sub> overexpression enhanced actinorhodin production in <i>Streptomyces coelicolor</i> and avermectin production in <i>Streptomyces avermitilis</i>, while inhibiting the biosynthesis of nemadectin and guvermectin in <i>Streptomyces cyaneogriseus</i> ssp. <i>noncyanogenus</i> and <i>Streptomyces caniferus</i>, respectively. These results expanded our understanding of the regulatory networks controlling SM biosynthesis in <i>Streptomyces</i> and provided beneficial regulatory targets for developing strategies to optimize SM yield.</p>

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Overexpression of the Wbl family regulator whiDsbh modulates secondary metabolite biosynthesis in Streptomyces

  • 期刊论文

  • 发表日期：

    2025年5月15日

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  • Xuedong Zhang,
  • Jiabin Wang,
  • Haoran Shi,
  • Na Zhou,
  • Shanshan Li,
  • Lan Ye,
  • Wensheng Xiang,
  • Xiangjing Wang,
  • Yanyan Zhang

摘要

Streptomyces species are prolific producers of a diverse array of bioactive secondary metabolites (SMs), which constitute approximately two-thirds of natural product-based pharmaceuticals with significant clinical, agricultural, and biotechnological applications. However, the regulatory mechanisms underlying the biosynthesis of these compounds remain poorly understood, impeding the development of high-yielding strains for industrial production. Herein, we investigated the role of the WhiB-like (Wbl) family transcriptional regulator, WhiDsbh, in modulating SM production in Streptomyces bingchenggensis BC04. Overexpression of whiDsbh in BC04 significantly suppressed milbemycin production by repressing the transcription of the milbemycin biosynthetic gene cluster via the ActK/R-KelR regulatory cascade. Comparative transcriptomic analysis between the whiDsbh overexpression strain and BC04 revealed that whiDsbh overexpression not only altered the expression of multiple other biosynthetic gene clusters but also impacted genes involved in central carbon metabolism, glutathione biosynthesis, and cofactor synthesis. Furthermore, cross-species genetic analysis demonstrated that whiDsbh overexpression enhanced actinorhodin production in Streptomyces coelicolor and avermectin production in Streptomyces avermitilis, while inhibiting the biosynthesis of nemadectin and guvermectin in Streptomyces cyaneogriseus ssp. noncyanogenus and Streptomyces caniferus, respectively. These results expanded our understanding of the regulatory networks controlling SM biosynthesis in Streptomyces and provided beneficial regulatory targets for developing strategies to optimize SM yield.