Microbial hormones as a master switch for secondary metabolism in streptomyces

Abstract

The genus Streptomyces can produce a wide variety of secondary metabolites, including antibiotics and other biologically active substances. These compounds are important starting scaffolds for the development of antibiotics, anthelminthic agents, anticancer agents, and immunosuppressants. Genome sequencing of some Streptomyces species has revealed that every Streptomyces strain has the potential to produce dozens of secondary metabolites, but only a fraction of these putative secondary metabolites are produced under standard fermentation conditions. Therefore, genetic approaches to engineering regulation are innovative ways to stimulate the expression of otherwise silent secondary metabolite gene clusters. In many Streptomyces species, γ-butyrolactone signaling molecules are used as a microbial hormone to induce secondary metabolite production. A-factor (2-isocapryloyl-3R-hydroxymethyl-γ-butyrolactone) is a representative γ-butyrolactone that triggers both morphological development and production of secondary metabolites, including streptomycin in Streptomyces griseus. Here, the A-factor regulatory cascade was reviewed with some results of our recent genome-wide analysis. Disruption of arpA, encoding the A-factor receptor protein ArpA, resulted in overproduction of streptomycin. Enhanced production of secondary metabolites by gene disruption of arpA homologues was also reported for other Streptomyces species. In addition, two other methods for the induction of secondary metabolite formation in Streptomyces are briefly described. New low molecular weight signaling molecules involved in the induction of secondary metabolite formation are also briefly described.