Deletion of a regulatory gene within the cpk gene cluster reveals novel antibacterial activity in Streptomyces coelicolor A3(2)

Abstract

Genome sequencing of Streptomyces coelicolor A3(2) revealed an uncharacterized type I polyketide synthase gene cluster (cpk). Here we describe the discovery of a novel antibacterial activity (abCPK) and a yellow-pigmented secondary metabolite (yCPK) after deleting a presumed pathway-specific regulatory gene (scbR2) that encodes a member of the c-butyrolactone receptor family of proteins and which lies in the cpk gene cluster. Overproduction of yCPK and abCPK in a scbR2 deletion mutant, and the absence of the newly described compounds from cpk deletion mutants, suggest that they are products of the previously orphan cpk biosynthetic pathway in which abCPK is converted into the yellow pigment. Transcriptional analysis suggests that scbR2 may act in a negative feedback mechanism to eventually limit yCPK biosynthesis. The results described here represent a novel approach for the discovery of new, biologically active compounds.

The role of two SARP family transcriptional regulators in regulation of the auricin gene cluster in Streptomyces aureofaciens CCM 3239

“…Kormanec, unpublished results). Therefore, Aur1R belongs to the family of the late represors, like the recently characterized homologues AlpW in S. ambofaciens (Bunet et al, 2011) and ScbR2 in Streptomyces coelicolor (Gottelt et al, 2010). The activation of the auricin cluster is then triggered by a signalling molecule (probably c-butyrolactone) in the late exponential phase (about 12 h), which, after binding to SagR, relieves repression of aur1P and aur1R.…”

The autoregulator receptor homologue AvaR3 plays a regulatory role in antibiotic production, mycelial aggregation and colony development of Streptomyces avermitilis

“…Second, a gene encoding an autoregulator receptor in the gene cluster for antibiotic biosynthesis simultaneously controls production of both the corresponding antibiotic and another antibiotic whose biosynthetic genes are distal to the locus of the receptor gene. Representative regulators of this type are ScbR (SCO6265) and ScbR2 (SCO6286) of Streptomyces coelicolor A3(2), which regulate the expression of a cryptic type I polyketide biosynthetic gene cluster (SCO6269-SCO6288) by repressing a pathway-specific regulatory gene, and indirectly stimulate production of actinorhodin and undecylprodigiosin (Gottelt et al, 2010;Takano et al, 2005). Third, an autoregulator receptor gene has no adjacent biosynthetic gene clusters but regulates the expression of antibiotic biosynthetic genes that are located apart from the locus of the receptor gene, as exemplified by ArpA of Streptomyces griseus.…”

jadR* and jadR2 act synergistically to repress jadomycin biosynthesis

“…The presence of multiple CSRs may reflect complex regulation in antibiotic biosynthesis. In the model organism S. coelicolor, two repressors (ScbR and ScbR2) and one activator (CpkO) were identified in the cpk cluster required for production of a polyketide-derived antibiotic, cryptic polyketide (CPK) [14,21]. CpkO is the direct activator for CPK biosynthesis, while ScbR and ScbR2 can repress the transcription of cpkO.…”