Phosphate Control of the Biosynthesis of Antibiotics and Other Secondary Metabolites Is Mediated by the PhoR-PhoP System: an Unfinished Story

The biosynthesis of many different types of antibiotics and other secondary metabolites is regulated by phosphate. Production of these valuable compounds occurs only under phosphate-limiting nutritional conditions. In a few cases, there is evidence showing that the negative phosphate control is exerted at the transcriptional level. Recently, it was shown that phosphate control of antibiotic biosynthesis in Streptomyces lividans and Streptomyces coelicolor is mediated by the two-component PhoR-PhoP system that also controls the alkaline phosphatase gene (phoA). The PhoR protein is a standard membrane sensor kinase, whereas PhoP is a member of the DNA-binding response regulators. In Escherichia coli and Bacillus subtilis, the phosphorylated PhoP protein (PhoP∼P) activates, in response to phosphate starvation, expression of the pho regulon genes by binding to consensus phosphate boxes in the promoter regions (PHO boxes). Expression of phoA in S. lividans is induced by PhoP∼P, and mutants lacking phoP (or phoR and phoP) do not form PhoA. These mutants overproduce large amounts of actinorhodin and undecylprodigiosin. No consensus PHO boxes occur in the upstream region of phosphate-regulated secondary metabolism genes. However, pathway-specific activator proteins (ActII-open reading frame 4 ORF4, RedD, CcaR, and DnrI) are known to bind to these regions. In S. coelicolor, actII-orf4 is positively regulated by the AfsS protein, which, in turn, is induced by the phosphorylated AfsR protein. It is likely that the PhoR-PhoP system exerts its action on actinorhodin and undecylprodigiosin by a cascade mechanism mediated by AfsR and AfsS. Directed phoR-phoP gene disruption will be very useful for the construction of tailored phosphate-deregulated strains overproducing valuable secondary metabolites.