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Background  The choice of phosphate/nitrogen source and their concentrations have been shown to have great influences on antibiotic production. However, the underlying mechanisms responsible for this remain poorly understood.    Results  We show that nutrient-sensing regulator PhoP (phosphate regulator) binds to and upregulates most of genes ( ery  cluster genes) involved in erythromycin biosynthesis in  Saccharopolyspora erythraea , resulting in increase of erythromycin yield. Furthermore, it was found that PhoP also directly interacted with the promoter region of  bldD  gene encoding an activator of erythromycin biosynthesis, and induced its transcription. Phosphate limitation and overexpression of  phoP  increased the transcript levels of  ery  genes to enhance the erythromycin production. The results are further supported by observation that an over-producing strain of  S. erythraea  expressed more PhoP than a wild-type strain. On the other hand, nitrogen signal exerts the regulatory effect on the erythromycin biosynthesis through GlnR negatively regulating the transcription of  phoP  gene.    Conclusions  These findings provide evidence that PhoP mediates the interplay between phosphate/nitrogen metabolism and secondary metabolism by integrating phosphate/nitrogen signals to modulate the erythromycin biosynthesis. Our study reveals a molecular mechanism underlying antibiotic production, and suggests new possibilities for designing metabolic engineering and fermentation optimization strategies for increasing antibiotics yield.

Phosphate regulator PhoP directly and indirectly controls transcription of the erythromycin biosynthesis genes in Saccharopolyspora erythraea