Clarification of mechanism for antibiotic production regulated by Streptomyces signaling molecules.

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Streptomyces species are gram-positive soil-dwelling filamentous bacteria that produce a wide variety of antibiotic and other secondary metabolites with important applications in human medicine and agriculture. These secondary metabolites are products of complex biosynthetic pathways including regulatory genes as well as their biosynthetic gene cluster. The activation of antibiotic production has been known to be controlled by the γ-butyrolactone autoregulator, a low-molecular-weight signaling molecule. Although the autoregulator-mediated mechanism has been partially clarified in many Streptomyces species, common trait has still remained unclear. In this research, we focused on framework for autoregulator-mediated mechanism by assembling information from each analysis. In Streptomyces virginiae, the autoregulator (VB) controls virginiamycin production by means of VB binding to VB receptor (BarA). Our analysis on BarB and BarZ, which possess moderate similarity to BarA, showed that virginiamycin production requires function of BarB and BarZ at initial or stationary phase, respectively. barB transcription is directly controlled by BarA binding to barB promoter region. In S.coelicolor A3(2), the model strain of Streptomyces species, autoregulator receptor was found to regulate directly transcriptional regulator, and thus controls expression of biosynthetic genes concerned with secondary metabolism. Moreover, we obtained 4 more autoregulator receptors from industrially important Streptomyces and non-Streptomyces strains. Taken together with these results, we conclude that useful information was successfully accumulated for industrial application.