In sp. FR-008, the biosynthetic gene cluster of the polyene antibiotic FR-008, also known as candicidin, consists of 21 genes, including four regulatory genes, . Our bioinformatics analyses indicate that FscRI has an N-terminal PAS domain, whereas the other three regulators have N-terminal AAA domains and are members of the LAL (large ATP-binding regulators of the LuxR type) family. Deletion of abolished the production of FR-008, with production restored in the complemented strain, supporting a critical role for FscRI in FR-008 biosynthesis. Consistent with these findings, transcription of genes involved in the biosynthesis and efflux of FR-008 was greatly downregulated in a Δ mutant. Interestingly, the regulatory gene was also downregulated in the Δ mutant. Production of FR-008 was reduced, but not abrogated, in an deletion mutant, and although structural genes were downregulated in Δ, the changes were much less dramatic than in Δ, suggesting a stronger regulatory role for FscRI. Remarkably, transcription of was also decreased in Δ. Expression of restored antibiotic production in a Δ mutant, but not vice versa. Putative binding sequences for FscRI were identified upstream of and the three structural genes , and , which encode large modular polyketide synthases. Our findings suggest that and are interregulatory, whereas expression of and appears to be independent of and . This study demonstrates that the regulation of polyene antibiotic synthesis can involve mutually regulated transcriptional activators that belong to different families.


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