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Antibacterial discovery in actinomycetes strains with mutations in RNA polymerase or ribosomal protein S12

Abstract

We show that selection of drug-resistant bacterial mutants allows the discovery of antibacterial compounds. Mutant strains of a soil-isolated Streptomyces species that does not produce antibacterials synthesize a previously unknown class of antibacterial, which we name piperidamycin. Overall, 6% of non-Streptomyces actinomycetes species and 43% of Streptomyces species that do not produce antibacterials are activated to produce them. The antibacterial-producing mutants all carried mutations in RNA polymerase and/or the ribosomal protein S12.

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Figure 1: Detection and analysis of antibacterial compounds produced by drug-resistant mutants of Streptomyces sp. 631689.
Figure 2: Functional analysis of mutant RNAPs and mutant ribosomes.

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Acknowledgements

This work was supported by a grant (to K.O.) from the Effective Promotion of Joint Research of Special Coordination Funds (Ministry of Education, Culture, Sports, Science, and Technology of the Japanese Government) and by an award (to T.H.) from the Bioscience Biotechnology and Agrochemistry Foundation. We are grateful to Haifeng Hu, Kazuhiko Kurosawa, Jun Xu, Hiroyuki Aoki and Dang T. Le for experimental contributions, and Tomoko Sato, Ikuko Maeda, Keiko Kubota, and Minako Ishihara for technical assistance.

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K.O. designed the project, analyzed the data and wrote the paper; T.H. performed all analyses of the strain 631689, isolated antibacterial compounds and wrote the paper; M.O.-K., S.K. and M.Y. determined chemical structure of piperidamycins and wrote the paper; H.M., K.M., Y.T. and A.F. isolated actinomycetes from soil and determined antibacterial productivity.

Corresponding author

Correspondence to Kozo Ochi.

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Supplementary Figures 1–4, Supplementary Tables 1–5 and Supplementary Methods (PDF 3489 kb)

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Hosaka, T., Ohnishi-Kameyama, M., Muramatsu, H. et al. Antibacterial discovery in actinomycetes strains with mutations in RNA polymerase or ribosomal protein S12. Nat Biotechnol 27, 462–464 (2009). https://doi.org/10.1038/nbt.1538

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