Salt supplementation-induced metabolic reprogramming in Streptomyces coelicolor

Members of the genus Streptomyces are major producers of a wide variety of secondary metabolites that serve as bioactive compounds. Many secondary metabolites are produced in response to environmental signals such as biotic and abiotic stresses. In this study, we identified salt supplementation as one of the stimuli activating secondary metabolism in the model Streptomyces species, Streptomyces coelicolor. Comparative metabolomics revealed overproduction of several known secondary metabolites, most notably undecylprodigiosin and coelimycin P1, in addition to their biosynthetic intermediates and derivatives, as well as many unknown metabolites. Transcriptomic analysis revealed activation of diverse biological processes including cation uptake, compatible solute production, and the phosphate limitation stress response through conserved and species-specific mechanisms, presumably to overcome the increased salinity. This response leads to activation of a variety of regulatory and metabolic pathways required for production of secondary metabolites including activation of conserved metabolic pathways for energy and substrate supply and species-specific secondary metabolite biosynthetic gene clusters. Furthermore, several promoter sequences contributing to upregulation of secondary metabolism induced by salt supplementation were identified. Overall, our data show how S. coelicolor copes with the increased salinity and tailors the cellular metabolism toward secondary metabolism in a conserved and species-specific manner.IMPORTANCEPrecise control of cellular metabolism is critical to ensure directing cellular resources toward metabolic pathways required for the environment. Many Streptomyces species activate production of secondary metabolites upon exposure to environmental stimuli. This study reveals dynamic reprogramming of cellular metabolism in Streptomyces coelicolor under increased salinity, which induces production of various secondary metabolites. Notably, this model biological system redirects cellular resources toward various metabolic pathways required for proper activation of secondary metabolite biosynthesis, including precursor and energy supply and posttranslational modification of biosynthetic enzymes. Interestingly, some pathways are activated by phosphate limitation stress, presumably caused as a result of increased salinity. Certain aspects of this metabolic reprogramming are likely common in many Streptomyces species and may be controlled by rather complex regulatory pathways. Overall, this study unveils how Streptomyces species tailor the cellular metabolism toward secondary metabolism and paves the way for understanding metabolic regulation.