NtcA—A negative regulator of secondary metabolite biosynthesis in Sorangium cellulosum

Microorganisms continue to be a source of novel, bioactive natural products for the treatment of human diseases. Notable among them are the myxobacteria, with some 50% of metabolites isolated from strains of a single species, Sorangium cellulosum. As native production in myxobacteria is often low, however, research has begun to address the regulatory systems governing the pathways, with the aim of increasing fermentation titers. These efforts are significantly enabled by whole genome sequencing data. We previously identified ChiR as a positive regulator of chivosazol biosynthesis in the genome sequencing strain S. cellulosum So ce56, only the second regulatory function known from myxobacterial secondary metabolism. As So ce56 is known to produce two additional compounds, the mixed polyketide etnangien ( Irschik et al., 2007 and Menche et al., 2008), and the siderophore myxochelin (Schneiker et al., 2007), we set out to further exploit the genome data to discover additional regulators of secondary metabolite biosynthesis. Here we report a novel function for a member of the NtcA family of nitrogen-responsive transcriptional regulators, as a negative transcriptional regulator of chivosazol biosynthesis. NtcA is a promoter binding protein (PBP), which recognizes a conserved sequence within the chivosazol promoter. Inactivation of ntcA enhanced the production of chivosazol by 4-fold, but also increased the yield of etnangien by 3.5-fold. The ammonia-induced repression of biosynthesis observed in wild type So ce56 was significantly attenuated in a ntcA mutant. Taken together, these data suggest that inhibition of chivosazol biosynthesis by environmental nitrogen is mediated, at least in part, by the NtcA protein. Our results also reinforce the idea that genomics-guided engineering of regulatory pathways is a viable strategy for improving metabolite yields through fermentation.