[3S06e] 22. Microbial Biotechnology

5:10 PM - 5:50 PM JST(8:10 AM - 8:50 AM UTC)

[2MBT-03-KL] Orchestrating Microbial Drugs Production in Streptomyces

Lingzhuo Zeng¹, Biwei Song¹, Powell Zhang², ○Lixin Zhang¹ (1. SKLBE, ECUST (China), 2. MIT (USA))

Keywords:

Streptomyces,Secondary metabolites,SMARTS (Streptomyces multiplexed artificial control system)

Streptomyces species are eminent producers of bioactive secondary metabolites (SMs, microbial drugs) with clinical, agricultural, and biotechnological applications. Industrial development of these strains necessitates an autoregulated reprogramming paradigm to orchestrate multi-target for maximal cellular contribution to SM biosynthesis; however, no such dynamic synchronicity technology is currently available. By leveraging the discovery that distinct quorum sensing (QS) receptors in Streptomyces genus can recognize an identical DNA binding site, we have built a QS-triggered promoter applicable across various Streptomyces species. Integrating this promoter with a stabilizer module and a multiplexer module, we further developed a Streptomyces multiplexed artificial control system (SMARTS) that can convert the transient signals of diverse QS into stable and multiplexed ON or OFF outputs with varying strengths. Using SMARTS, we established a multi-objective optimization framework that synergistically fine-tunes targets synchronously to enhance SM production. We demonstrated the applications of this SMARTS-based reprogramming by developing two Streptomyces strains: a re-designed native Streptomyces avermitilis for specialized production of the nematicide baiweimectin, and a de novo programmed Streptomyces venezuelae for heterologous production of the currently semi-synthesized antitumor drug epidoxorubicin. Notably, the baiweimectin-producing strain was scaled up to 120-m³ industrial-scale fermentation with the titer of 8.4 gl^-1, underscoring the robustness of the SMARTS-based program. Our work provides a dynamic synchronicity paradigm for overproduction of Streptomyces microbial drugs.