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Ribosome engineering and fermentation optimization leads to overproduction of tiancimycin A, a new enediyne natural product from Streptomyces sp. CB03234

  • Fermentation, Cell Culture and Bioengineering - Original Paper
  • Published:
Journal of Industrial Microbiology & Biotechnology

Abstract

Tiancimycin (TNM) A, a recently discovered enediyne natural product from Streptomyces sp. CB03234, showed rapid and complete killing of cancer cells and could be used as a payload in antibody drug conjugates. The low yield of TNM A in the wild-type strain promoted us to use ribosome engineering and fermentation optimization for its yield improvement. The Streptomyces sp. CB03234-R-16 mutant strain with a L422P mutation in RpoB, the RNA polymerase β-subunit, was obtained from the rifamycin-resistant screening. After fermentation optimization, the titers of TNM A in Streptomyces sp. CB03234-R-16 reached to 22.5 ± 3.1 mg L−1 in shaking flasks, and 13 ± 1 mg L−1 in 15 L fermentors, which were at least 40-fold higher than that in the wild-type strain (~ 0.3 mg L−1). Quantitative real-time RT-PCR revealed markedly enhanced expression of key genes encoding TNM A biosynthetic enzymes and regulators in Streptomyces sp. CB03234-R-16. Our study should greatly facilitate the future efforts to develop TNM A into a clinical anticancer drug.

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Acknowledgements

This work was supported in parts by NSFC Grants 81473124 (to Y.H.), 81530092 (to B.S.), the Chinese Ministry of Education 111 Project B0803420 (to Y.D.), NIH Grants GM115575 and CA204484 (to B.S.).

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Author notes

  1. Ling Liu and Jian Pan contributed equally.

Authors and Affiliations

  1. Xiangya International Academy of Translational Medicine, Central South University, Changsha, 410013, Hunan, China

    Ling Liu, Jian Pan, Zilong Wang, Xiangcheng Zhu, Yanwen Duan & Yong Huang

  2. Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Xiangcheng Zhu, Yanwen Duan & Yong Huang

  3. Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, 410011, Hunan, China

    Xiangcheng Zhu & Yanwen Duan

  4. National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery, Changsha, 410011, Hunan, China

    Yanwen Duan & Yong Huang

  5. Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA

    Xiaohui Yan, Dong Yang & Ben Shen

  6. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA

    Ben Shen

  7. Natural Products Library Initiative, The Scripps Research Institute, Jupiter, FL, 33458, USA

    Ben Shen

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  1. Ling Liu
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Liu, L., Pan, J., Wang, Z. et al. Ribosome engineering and fermentation optimization leads to overproduction of tiancimycin A, a new enediyne natural product from Streptomyces sp. CB03234. J Ind Microbiol Biotechnol 45, 141–151 (2018). https://doi.org/10.1007/s10295-018-2014-8

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