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<p><i>Streptomyces</i> species are producers of bioactive secondary metabolites with clinical, agricultural and biotechnological applications. To scale these strains for industrial production, a plug-and-play system that orchestrates multitarget engineering for maximizing cellular contributions to secondary metabolites is needed. Building on the discovery that distinct quorum-sensing receptors within the <i>Streptomyces</i> genus can recognize an identical DNA-binding site, we build a quorum-sensing-triggered promoter applicable across various <i>Streptomyces</i>. Integrating this promoter with a stabilizer and a multiplexer module, we develop a <i>Streptomyces</i> multiplexed artificial control system (SMARTS) that converts the transient signals of diverse quorum sensing into stable and multiplexed on or off outputs with varying strengths. We build a redesigned native <i>Streptomyces avermitilis</i> for specialized production of the nematicide baiweimectin and a de novo programmed <i>Streptomyces venezuelae</i> for heterologous production of the semisynthesized antitumor drug epidoxorubicin. Notably, the baiweimectin-producing strain was scaled up to a 120-m<sup>3</sup> industrial-scale fermentation with a titer of 8.4 g L<sup>−1</sup>, underscoring the robustness of the SMARTS-based program.</p>

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Scalable secondary metabolite production in Streptomyces using a plug-and-play system

  • 期刊论文

  • 发表日期：

    2025年8月15日

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  • Bowen Yang,
  • Zilong Li,
  • Jingyu Zhang,
  • Shiwen Qiu,
  • Xueting Liu,
  • Zonglin Liang,
  • Hao Yan,
  • Yanyan Zhang,
  • Lihong Liu,
  • Bing Xia,
  • Lianqun Bao,
  • Defeng Li,
  • Shanshan Zhou,
  • Christophe Corre,
  • Chengyu Zhang,
  • Yinhua Lu,
  • Gao-Yi Tan,
  • Xuekui Xia,
  • Shanshan Li,
  • Lixin Zhang,
  • Weishan Wang

摘要

Streptomyces species are producers of bioactive secondary metabolites with clinical, agricultural and biotechnological applications. To scale these strains for industrial production, a plug-and-play system that orchestrates multitarget engineering for maximizing cellular contributions to secondary metabolites is needed. Building on the discovery that distinct quorum-sensing receptors within the Streptomyces genus can recognize an identical DNA-binding site, we build a quorum-sensing-triggered promoter applicable across various Streptomyces. Integrating this promoter with a stabilizer and a multiplexer module, we develop a Streptomyces multiplexed artificial control system (SMARTS) that converts the transient signals of diverse quorum sensing into stable and multiplexed on or off outputs with varying strengths. We build a redesigned native Streptomyces avermitilis for specialized production of the nematicide baiweimectin and a de novo programmed Streptomyces venezuelae for heterologous production of the semisynthesized antitumor drug epidoxorubicin. Notably, the baiweimectin-producing strain was scaled up to a 120-m3 industrial-scale fermentation with a titer of 8.4 g L−1, underscoring the robustness of the SMARTS-based program.