Decoding multidimensional regulatory networks in Streptomyces to accelerate natural product discovery and production

Covering: 2019 to 2025Streptomyces species are well known for their immense genomic potential for the discovery of natural products. However, the majority of their biosynthetic gene clusters (BGCs) remain silent or are poorly expressed under laboratory conditions. This silence is largely attributed to the regulatory complexity encoded within their large genomes, which feature thousands of regulators and multilayered control systems. In this review, we summarize the current knowledge regarding genome-scale transcriptional regulation in Streptomyces, alongside the emerging experimental platforms designed to investigate these mechanisms. By integrating and comparing fragmented data on regulatory architectures, we highlight the extensive hierarchical, combinatorial, and condition-dependent regulatory networks that govern secondary metabolite biosynthesis in Streptomyces. Furthermore, integrative analyses reveal the conservation of regulatory architectures across Streptomyces species, facilitating the translation of findings from model organisms to BGC discovery, activation, and engineering in less studied species. Beyond transcription, we also discuss the additional regulatory layers, including post-transcriptional, translational, post-translational, and chromosome topology-based controls, and their practical applications in natural product research. Collectively, this review reframes the complex transcriptional regulatory networks not as a bottleneck but as a central principle for understanding and exploiting the biosynthetic potential of Streptomyces.