Activation of silent biosynthetic gene clusters using transcription factor decoys

Here we report a transcription factor decoy strategy for targeted activation of eight large silent polyketide synthase and non-ribosomal peptide synthetase gene clusters, ranging from 50 to 134 kilobases (kb) in multiple streptomycetes, and characterization of a novel oxazole family compound produced by a 98-kb biosynthetic gene cluster. Owing to its simplicity and ease of use, this strategy can be scaled up readily for discovery of natural products in streptomycetes. Transcription factor decoys, DNA molecules designed to mimic regulatory DNAs and prevent repressors binding to their DNA targets, are used to achieve de-repression of silent biosynthetic gene clusters, resulting in production of new natural products.