Genetic and transcriptional analysis of absA, an antibiotic gene cluster-linked two-component system that regulates multiple antibiotics in Streptomyces coelicolor

In Streptomyces coelicolor, the AbsA1-AbsA2 two-component system regulates the expression of multiple antibiotic gene clusters. Here, we show that the response regulator encoded by the absA2 gene is a negative regulator of these antibiotic gene clusters, A genetic analysis shows that the phosphorylated form of the AbsA2 response regulator (phospho-AbsA2), generated by the cognate AbsA1 sensor histidine kinase, is required for normal growth phase regulation of antibiotic synthesis. In the absence of phospho-AbsA2, antibiotics are produced earlier and more abundantly. Overexpression of AbsA1 also deregulates antibiotic synthesis, apparently shifting the AbsA1 protein from a kinase-active to a phospho-AbsA2 phosphatase-active form. The absA1 and absA2 genes, which are adjacent, are located in one of the antibiotic gene clusters that they regulate, the cluster for the calcium-dependent antibiotic (CDA). The absA genes themselves are growth phase regulated, with phospho-AbsA2 responsible for growth phase-related positive autoregulation. We discuss the possible role and mechanism of AbsA-mediated regulation of antibiotic synthesis in the S. coelicolor life cycle.