Scalable secondary metabolite production in Streptomyces using a plug-and-play system.
basic_science · Level V
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- Record sourced from PubMed, PMID 40817351.
- Also identified by DOI 10.1038/s41587-025-02762-1.
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Abstract
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-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.