Development of an endogenous quorum-sensing based bifunctional dynamic regulation system for efficient product synthesis in Streptomyces

Mengyao Yang; Yifan Zhao; Ruihui Huang; Xuejin Zhao; Ying Wen

doi:10.1016/j.biortech.2025.132898

Development of an endogenous quorum-sensing based bifunctional dynamic regulation system for efficient product synthesis in Streptomyces

Bioresour Technol. 2025 Jun 26:132898. doi: 10.1016/j.biortech.2025.132898. Online ahead of print.

Authors

Mengyao Yang¹, Yifan Zhao¹, Ruihui Huang¹, Xuejin Zhao², Ying Wen³

Affiliations

¹ State Key Laboratory of Animal Biotech Breeding and College of Biological Sciences, China Agricultural University, Beijing 100193, China.
² CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: zhaoxj@im.ac.cn.
³ State Key Laboratory of Animal Biotech Breeding and College of Biological Sciences, China Agricultural University, Beijing 100193, China. Electronic address: wen@cau.edu.cn.

PMID: 40581056
DOI: 10.1016/j.biortech.2025.132898

Abstract

Streptomyces species are known for producing a great variety of commercially valuable secondary metabolites, especially antibiotics. However, engineering ofStreptomycesis inflexible due to the lack of dynamic regulation tools. The effective endogenous quorum-sensing (QS) circuits capable of simultaneously and dynamically up- and down-regulating different sets of genes for efficient product synthesis have not yet been developed. Here, by leveraging the endogenous avenolide-mediated QS system, we designed a bifunctional dynamic regulation system in avermectin (AVE)-producing Streptomyces avermitilis, enabling simultaneous dynamic up- and down-regulation of multiple target genes. Using the dynamic up-regulation circuit, we up-regulated key genes involved in precursor supply for AVE production, resulting in a 727.4 % increase in AVE B1a (the most effective AVE component) titer in wild-type (WT) strain. Using the dynamic down-regulation circuit to down-regulate key node genes in TCA cycle, aspartate degradation, and acetate synthesis pathways for redirecting metabolic flux toward AVE production resulted in a 589.6 % increase in B1a titer in WT strain. Combined application of the dynamic up- and down-regulation circuits in WT and high-yield industrial strain A229 resulted in B1a titers 413.9 μg/mL (858.1 % higher than WT value) and 8067.6 μg/mL (25.7 % higher than A229 value). These findings present a novel bifunctional dynamic regulation strategy for strain improvement, with the potential to be easily adapted to other microorganisms with identified endogenous QS systems.

Keywords: Avermectin; Dynamic regulation; Quorum-sensing; Secondary metabolite; Streptomyces.