Abstract
Streptomyces avermitilis is an important bacterial species used for industrial production of avermectins, a family of broad-spectrum anthelmintic agents. We previously identified the protein SAV576, a TetR family transcriptional regulator (TFR), as a downregulator of avermectin biosynthesis that acts by controlling transcription of its major target gene SAV575 (which encodes cytochrome P450/NADPH-ferrihemoprotein reductase) and ave genes. SAV577, another TFR gene, encodes a SAV577 protein that displays high amino acid homology with SAV576. In this study, we examined the effect of SAV577 on avermectin production and the relationships between SAV576 and SAV577. SAV577 downregulated avermectin biosynthesis indirectly, similarly to SAV576. SAV576 and SAV577 both directly repressed SAV575 transcription, and reciprocally repressed each other's expression. SAV575 transcription levels in various S. avermitilis strains were correlated with avermectin production levels. DNase I footprinting and electrophoretic mobility shift assays indicated that SAV576 and SAV577 compete for the same binding regions, and that DNA-binding affinity of SAV576 is much stronger than that of SAV577. GST pull-down assays revealed no direct interaction between the two proteins. Taken together, these findings suggest that SAV577 regulates avermectin production in S. avermitilis by a mechanism similar to that of SAV576, and that the role of SAV576 is dominant over that of SAV577. This is the first report of two adjacent and similar TFR genes that co-regulate antibiotic production in Streptomyces.
Highlights
Streptomyces bacteria produce a wide range of bioactive secondary metabolites during their complex life cycle
In view of the similarity of TFRs SAV577 and SAV576, we investigated the possible role of SAV577 in avermectin production
Avermectin production was restored in this complementation strain, confirming that the absence of SAV577 was the cause of enhanced avermectin production in D577
Summary
Streptomyces bacteria produce a wide range of bioactive secondary metabolites during their complex life cycle. These metabolites include source compounds for most known antibacterial, anticancer, anthelmintic, and immunosuppressive antibiotics [1,2,3]. The biosynthesis of these antibiotics is under the control of numerous regulatory factors, including environmental and physiological factors, pathway-specific and pleiotropic regulatory factors [4,5,6,7,8,9,10]. The regulatory factors and mechanisms involved in avermectin production are poorly known Increased understanding of these factors and mechanisms will be useful in generating antibiotic overproducers, inhibiting production of undesired antibiotics, and activating production of cryptic antibiotics
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