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

Publisher Website
Google Scholar
Abstract
The negative control exerted by inorganic phosphate on the biosynthesis of antibiotics and other secondary metabolites has been known for many years. Over the last four decades, an impressive number of antibiotics and secondary metabolites have been shown to be regulated negatively by phosphate. These include streptomycin, oxytetracycline, clavulanic acid, tylosin, echinomycin, cephalosporin, cephamycin C, and thienamycin, among many other secondary metabolites (23, 27, 32), but, surprisingly, the molecular mechanism of phosphate control has remained obscure (30) in spite of its basic and industrial relevance. It is interesting that inorganic phosphate in the culture medium controls the synthesis of a large number of secondary metabolites belonging to different biosynthetic groups such as, for example, macrolides, tetracyclines, anthracyclines, polyether compounds, aminoglycosides, and amino acid-derived metabolites such as clavulanic acid, among others (10, 11, 15, 16, 25). Why are all these compounds repressed by high concentrations of inorganic phosphate? From a biosynthetic point of view, these groups of metabolites have very little in common, except that they all are dispensable “secondary” metabolites. The negative effect exerted by inorganic phosphate on the biosynthesis of secondary metabolites is observed in a wide range of microorganisms, including proteobacteria, gram-positive bacteria (e.g., actinomycetes), and filamentous fungi, and probably has a wide ecological role. Martín and Demain proposed that phosphate control is used as a mechanism that triggers secondary metabolite biosynthesis when phosphate in the environment is depleted and, therefore, growth of the microorganisms cannot proceed at a normal rate (28). When the phosphate concentration in the culture medium decreases below a threshold level, bacteria increase their production of a variety of metabolites that might serve as direct antagonists to other microorganisms (48) or as biochemical cross talk signals (17, 38, 51) to enhance survival under harsh nutritional conditions (26).