Streptomyces species produce an incredible array of high-value specialty chemicals and medicinal therapeutics. A single species typically harbors ~30 biosynthetic pathways, but only a mere handful of them are expressed in the laboratory, thus poor understanding of how natural products biosynthesis is regulated is a major bottleneck in drug discovery. Antimycins are a large family of anticancer compounds widely produced by Streptomyces species and their regulation is atypical compared to that of most other natural products. Here we demonstrate that antimycin production by Streptomyces albus S4 is regulated by FscRI, a PAS-LuxR-family cluster-situated regulator of the polyene antifungal agent, candicidin. We report that heterologous production of antimycins by Streptomyces coelicolor is dependent on FscRI and show that FscRI activates transcription of key biosynthetic genes. We also demonstrate through ChIP sequencing that FscRI regulation is direct and we provide evidence to suggest that this regulation strategy is conserved and unique to short form antimycin gene clusters. Our study provides direct in vivo evidence for cross-regulation of disparate biosynthetic gene clusters specifying unrelated natural products and expands the paradigmatic understanding of the regulation of secondary metabolism.
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