| Summary: | Daptomycin, produced by <i>Streptomyces roseosporus</i>, is a clinically important cyclic lipopeptide antibiotic used for the treatment of human infections caused by drug-resistant Gram-positive pathogens. In contrast to most <i>Streptomyces</i> antibiotic biosynthetic gene clusters (BGCs), daptomycin BGC has no cluster-situated regulator (CSR) genes. DasR, a GntR-family transcriptional regulator (TR) widely present in the genus, was shown to regulate antibiotic production in model species <i>S. coelicolor</i> by binding to promoter regions of CSR genes. New findings reported here reveal that DasR pleiotropically regulates production of daptomycin and reddish pigment, and morphological development in <i>S. roseosporus. dasR</i> deletion enhanced daptomycin production and morphological development, but reduced pigment production. DasR inhibited daptomycin production by directly repressing <i>dpt</i> structural genes and global regulatory gene <i>adpA</i> (whose product AdpA protein activates daptomycin production and morphological development). DasR-protected regions on <i>dptEp</i> and <i>adpAp</i> contained a 16 nt sequence similar to the consensus DasR-binding site <i>dre</i> in <i>S. coelicolor</i>. AdpA was shown to target <i>dpt</i> structural genes and <i>dptR2</i> (which encodes a DeoR-family TR required for daptomycin production). A 10 nt sequence similar to the consensus AdpA-binding site was found on target promoter regions <i>dptAp</i> and <i>dptR2p</i>. This is the first demonstration that DasR regulates antibiotic production both directly and through a cascade mechanism. The findings expand our limited knowledge of the regulatory network underlying daptomycin production, and will facilitate methods for construction of daptomycin overproducers.
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