Source  NATURE BIOTECHNOLOGY

Early Access  AUG 2025

DOI:  10.1038/s41587-025-02762-1

IF  41.7

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 systemthat 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.