AdpA, A Global Regulator of Hundreds of Genes, Including Those for Secondary Metabolism, in Streptomyces venezuelae

Background: Streptomyces bacteria are prolific producers of secondary metabolites (SMs), including many antibiotics. However, most biosynthetic gene clusters (BGCs) remain silent under laboratory conditions. Global transcriptional regulators, such as AdpA, can activate these BGCs, but their roles in secondary metabolism are not fully understood. This study investigates the regulatory function of AdpA in Streptomyces venezuelae (AdpA_Sv), a fast-growing model species and natural chloramphenicol producer that encodes over 30 BGCs. Methods: We applied RNA-seq and ChIP-seq at 12 and 20 h—corresponding to vegetative and aerial hyphae stages—to profile the AdpA_Sv regulatory network. Results: AdpA_Sv influenced the expression of approximately 3000 genes, including those involved in primary metabolism, quorum sensing, sulfur metabolism, ABC transporters, and all annotated BGCs, and it bound to around 200 genomic sites. Integration of RNA-seq and ChIP-seq data identified a core regulon of 49–91 directly regulated genes, with additional effects likely mediated indirectly via other transcription factors or non-canonical binding sites. Motif analysis confirmed similarity to the canonical Streptomyces griseus AdpA-binding sequence, with a novel 5-bp 3′ extension. AdpA_Sv directly regulated several SM pathways, including chloramphenicol biosynthesis, potentially alleviating Lsr2-mediated repression. Conclusions: This study defines, for the first time, the direct AdpA regulon in S. venezuelae and establishes AdpA_Sv as a central regulator of secondary metabolism. Our findings highlight S. venezuelae as a promising chassis strain for heterologous expression and suggest strategies for activating silent BGCs in other Streptomyces species.