Activation of silent biosynthetic gene clusters using transcription factor decoys

Abstract

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.

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Fig. 1: Workflow of the TFD strategy.
Fig. 2: Activation of BGCs in two streptomycetes.

Data availability

The DNA sequence encoding the oxazolepoxidomycin biosynthetic gene cluster from Streptomyces sp. NRRL F-4335 has been deposited to GenBank with accession code BK010686. All other data pertaining to this study are contained in the published article and its Supplementary Information files or are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grant GM077596 (to H.Z.) from the US National Institutes of Health (NIH). Some of the data were collected in the Carl R. Woese Institute for Genomic Biology Core on a 600 MHz NMR funded by NIH grant number S10-RR028833, LC-MS at the MCB Metabolomics Center, and HRMS at the SCS Mass Spectrometry Laboratory. B.W. and F.G. dedicate this article to the memory of Keqian Yang, who made important contributions to their understanding of Streptomyces genetic regulation of secondary metabolism.

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B.W. and H.Z. conceived and designed the study, and wrote the manuscript. B.W. and F.G. performed the experiments and analysed the data, and purified compounds. B.W. and S.-H.D. analyzed the NMR data.

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Correspondence to Huimin Zhao.

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The authors declare no competing interests.

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Supplementary Tables 1–6, Supplementary Figures 1–10, Supplementary Notes 1 and 2

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Wang, B., Guo, F., Dong, S. et al. Activation of silent biosynthetic gene clusters using transcription factor decoys. Nat Chem Biol 15, 111–114 (2019). https://doi.org/10.1038/s41589-018-0187-0

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