Abstract
Avermectins produced by Streptomyces avermitilis are potent anti-parasitic agents that are useful in animal health care, agriculture, and the treatment of human infections. In a search for novel regulators that affect avermectin biosynthesis, comparative transcriptome analysis was performed between wild-type strain ATCC31267 and avermectin overproducing strain 76-02-e, revealing some differentially expressed genes. SAV576, which is downregulated in 76-02-e and encodes a TetR family transcriptional regulator (TFR), was shown to inhibit avermectin production by indirectly affecting the expression of ave genes. SAV576 directly repressed the transcription of its gene SAV576 and of adjacent genes SAV575 (encodes cytochrome P450/NADPH-ferrihemoprotein reductase) and SAV574. The SAV576-binding sites within the bidirectional SAV575-SAV576 promoter region were determined by DNase I footprinting assays. A consensus 15-bp palindromic sequence CCRTACRVYGTATGS was found in these binding sites and shown to be important for SAV576-binding activity. SAV575, an important target gene of SAV576, was shown to exert a positive effect on avermectin production. The study findings extend our limited knowledge of the complex regulation of avermectin biosynthesis and provide a basis for rational genetic manipulation of S. avermitilis to improve avermectin production through control of SAV576 and its target gene.
Highlights
Streptomyces species are gram-positive filamentous soil bacteria known for their ability to produce a wide range of bioactive secondary metabolites during their complex life cycle
The growth and avermectin production of D576/pSET152-576 were both similar to those of ATCC31267. These findings indicate that SAV576 acts to inhibit avermectin biosynthesis, but has no effect on cell growth
SAV575 Exerts a Positive Effect on Avermectin Production Because SAV575 was found to be a target gene of SAV576, we further investigated its relationship with avermectin production
Summary
Streptomyces species are gram-positive filamentous soil bacteria known for their ability to produce a wide range of bioactive secondary metabolites during their complex life cycle. These metabolites include many useful antibiotics that display antibacterial, anticancer, anthelmintic, and/or immunosuppressive activities [1,2]. Avermectins are a series of potent anthelmintic and insecticidal macrolide antibiotics (A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b) produced by S. avermitilis. They are used commercially for broad-spectrum parasite control in medical, veterinary, and agricultural fields [17,18]. Further studies are required to identify other yet-unknown regulatory genes, which will contribute to better understanding of the regulatory networks of avermectin biosynthesis and to the practical construction of avermectin high-producing strains
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