Activation and enhancement of Fredericamycin A production in deepsea-derived Streptomyces somaliensis SCSIO ZH66 by using ribosome engineering and response surface methodology
Zhang, Yonghe1; Huang, Huiming1; Xu, Shanshan1; Wang, Bo1; Ju, Jianhua1; Tan, Huarong1; Li, Wenli1; liwenli@ouc.edu.cn
2015
发表期刊MICROBIAL CELL FACTORIES
卷号14页码:64-
摘要Background: Marine microorganisms are an important source of new drug leads. However, the discovery and sustainable production of these compounds are often hampered due to the unavailable expression of cryptic biosynthetic gene clusters or limited titer. Ribosome engineering and response surface methodology (RSM) integrated strategy was developed in this study to activate cryptic gene cluster in the deepsea-derived Streptomyces somaliensis SCSIO ZH66, and subsequently isolation, structural analysis, and the yield enhancement of the activated compound, anticancer drug lead Fredericamycin A (FDM A), were performed. Results: In order to discover novel natural products from marine Streptomyces strains by genome mining strategy, the deepsea-derived Streptomyces somaliensis SCSIO ZH66 was subject to ribosome engineering to activate the expression of cryptic gene clusters. A resistant strain ZH66-RIF1 was thereby obtained with 300 mu g/mL rifampicin, which accumulated a brown pigment with cytotoxicity on MS plate while absent in the wild type strain. After screening of fermentation conditions, the compound with pigment was purified and identified to be FDM A, indicating that the activation of a cryptic FDM A biosynthetic gene cluster was taken place in strain ZH66-RIF1, and then it was identified to be ascribed to the mutation of R444H in the beta subunit of RNA polymerase. To further improve the yield efficiently, nine fermentation medium components were examined for their significance on FDM A production by Plackett-Burman design and Box-Behnken design. The optimum medium composition was achieved by RSM strategy, under which the titer of FDM A reached 679.5 +/- 15.8 mg/L after 7 days of fermentation, representing a 3-fold increase compared to the original medium. In terms of short fermentation time and low-cost fermentation medium, strain ZH66-RIF1 would be an ideal alternative source for FDM A production. Conclusions: Our results would hasten the efforts for further development of FDM A as a drug candidate. Moreover, this ribosome engineering and RSM integrated methodology is effective, fast and efficient; it would be applicable to genome mining for novel natural products from other strains.
部门归属LMB
关键词Deepsea-derived Streptomyces Ribosome Engineering Cryptic Gene Cluster Response Surface Methodology (Rsm) Fredericamycin a (Fdm a)
学科领域Biotechnology & Applied Microbiology
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文献类型期刊论文
条目标识符http://ir.scsio.ac.cn/handle/344004/14836
专题中科院海洋生物资源可持续利用重点实验室
通讯作者liwenli@ouc.edu.cn
作者单位1.[Zhang, Yonghe
2.Huang, Huiming
3.Xu, Shanshan
4.Li, Wenli] Ocean Univ China, Sch Med & Pharm, Minist Educ China, Key Lab Marine Drugs, Qingdao 266003, Peoples R China
5.[Wang, Bo
6.Ju, Jianhua] Chinese Acad Sci, CAS Key Lab Marine Bioresources Sustainable Utili, Guangdong Key Lab Marine Mat Med, South China Sea Inst Oceanol,RNAM Ctr Marine Micr, Guangzhou 510301, Guangdong, Peoples R China
7.[Tan, Huarong] Chinese Acad Sci, Inst Microbiol, State Key Lab Microbial Resources, Beijing 100101, Peoples R China
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Zhang, Yonghe,Huang, Huiming,Xu, Shanshan,et al. Activation and enhancement of Fredericamycin A production in deepsea-derived Streptomyces somaliensis SCSIO ZH66 by using ribosome engineering and response surface methodology[J]. MICROBIAL CELL FACTORIES,2015,14:64-.
APA Zhang, Yonghe.,Huang, Huiming.,Xu, Shanshan.,Wang, Bo.,Ju, Jianhua.,...&liwenli@ouc.edu.cn.(2015).Activation and enhancement of Fredericamycin A production in deepsea-derived Streptomyces somaliensis SCSIO ZH66 by using ribosome engineering and response surface methodology.MICROBIAL CELL FACTORIES,14,64-.
MLA Zhang, Yonghe,et al."Activation and enhancement of Fredericamycin A production in deepsea-derived Streptomyces somaliensis SCSIO ZH66 by using ribosome engineering and response surface methodology".MICROBIAL CELL FACTORIES 14(2015):64-.
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