Negative regulation of daptomycin production by DepR2, an ArsR-family transcriptional factor

Daptomycin, a lipopeptide antibiotic potently active against Gram-positive bacterial pathogens, is produced by Streptomyces roseosporus , but the transcriptional regulation on its biosynthesis is not fully understood. Here, we report that DepR2, an ArsR-family transcriptional regulator isolated previously by DNA-affinity purification, interacts directly with dptEp , the major promoter of the daptomycin gene cluster. DepR2 binds to an imperfect palindromic sequence at the very upstream of dptEp . Meanwhile, higher dptEp activities were consistently observed in the ΔdepR2 mutant, correlating with a nearly 2.5-fold increased production of daptomycin and three structurally related secondary metabolites A21978C 1–3 . Thus, our data suggest that the ArsR-family transcriptional regulator DepR2 negatively regulates production of daptomycin by directly repressing the expression of its gene cluster in S. roseosporus . To the best of our knowledge, this is the first report to show the involvement of an ArsR-family regulator in the direct regulation of secondary metabolite biosynthesis in Streptomyces .