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 A21978C1-3. 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.