Bacterial Competition Reveals Differential Regulation of the pks Genes by Bacillus subtilis

Bacillus subtilis is adaptable to many environments in part due to its ability to produce a broad range of bioactive compounds. One such compound, bacillaene, is a linear polyketide/nonribosomal peptide. Thepks genes encode the enzymatic megacomplex that synthesizes bacillaene. The majority ofpks genes appear to be organized as a giant operon (>74 kb frompksC-pksR ). In previous work (P. D. Straight, M. A. Fischbach, C. T. Walsh, D. Z. Rudner, and R. Kolter, Proc. Natl. Acad. Sci. U. S. A. 104:305–310, 2007, doi:10.1073/pnas.0609073103), a deletion of thepks operon inB. subtilis was found to induce prodiginine production byStreptomyces coelicolor . Here, colonies of wild-typeB. subtilis formed a spreading population that induced prodiginine production fromStreptomyces lividans , suggesting differential regulation ofpks genes and, as a result, bacillaene. While the parent colony showed widespread induction ofpks expression among cells in the population, we found the spreading cells uniformly and transiently repressed the expression of thepks genes. To identify regulators that controlpks genes, we first determined the pattern ofpks gene expression in liquid culture. We next identified mutations in regulatory genes that disrupted the wild-type pattern ofpks gene expression. We found that expression of thepks genes requires the master regulator of development, Spo0A, through its repression of AbrB and the stationary-phase regulator, CodY. Deletions ofdegU ,comA , andscoC had moderate effects, disrupting the timing and level ofpks gene expression. The observed patterns of expression suggest that complex regulation of bacillaene and other antibiotics optimizes competitive fitness forB. subtilis .