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

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

  • J Ind Microbiol Biotechnol. 2018 Mar;45(3):141-151. doi: 10.1007/s10295-018-2014-8.
Ling Liu 1,  Jian Pan 1,  Zilong Wang 1,  Xiaohui Yan 2,  Dong Yang 2,  Xiangcheng Zhu 1 3 4,  Ben Shen 2 5 6,  Yanwen Duan 7 8 9 10,  Yong Huang 11 12 13
Affiliations

Affiliations

  • 1 Xiangya International Academy of Translational Medicine, Central South University, Changsha, 410013, Hunan, China.
  • 2 Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA.
  • 3 Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 4 Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, 410011, Hunan, China.
  • 5 Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
  • 6 Natural Products Library Initiative, The Scripps Research Institute, Jupiter, FL, 33458, USA.
  • 7 Xiangya International Academy of Translational Medicine, Central South University, Changsha, 410013, Hunan, China. ywduan66@sina.com.
  • 8 Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. ywduan66@sina.com.
  • 9 Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, 410011, Hunan, China. ywduan66@sina.com.
  • 10 National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery, Changsha, 410011, Hunan, China. ywduan66@sina.com.
  • 11 Xiangya International Academy of Translational Medicine, Central South University, Changsha, 410013, Hunan, China. jonghuang@csu.edu.cn.
  • 12 Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. jonghuang@csu.edu.cn.
  • 13 National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery, Changsha, 410011, Hunan, China. jonghuang@csu.edu.cn.
PMID: 29396746 DOI: 10.1007/s10295-018-2014-8
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.

Keywords

Enediyne natural product; In situ resin adsorption; Ribosome engineering; RpoB; Tiancimycin A.

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