文献类型：期刊文献

英文题名：Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228

作者：Liu, Xiangyang[1,2];Xie, Feng[3];Doughty, Leah B.[4];Wang, Qi[3];Zhang, Lixin[1,3];Liu, Xueting[1];Cheng, Yi-Qiang[2,4]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Univ North Texas, UNT Syst Coll Pharm, Hlth Sci Ctr, Ft Worth, TX 76107 USA;[3]Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China;[4]Univ Wisconsin, Dept Biol Sci, POB 413, Milwaukee, WI 53201 USA

年份：2018

卷号：3

期号：4

起止页码：268

外文期刊名：SYNTHETIC AND SYSTEMS BIOTECHNOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000451425500010)】；

基金：We dedicate this paper to and in memory of our beloved friend and colleague, Prof. Keqiang Yang, who devoted his life to the research on Streptomyces physiology, antibiotic biosynthesis, and molecular regulation. This work was supported in parts by a Catalyst Award from the University of Wisconsin-Milwaukee Research Foundation and a Public Health Service grant (CA152212) from the National Cancer Institute to YQC, the National Science Foundation of China (31430002, 31770055, 31570031), the Fundamental Research Funds for the Central Universities (22221818014), the Major Basic Program of the Natural Science Foundation of Shandong Province (ZR2017ZB0206), and the Shandong Taishan Scholar Program of China to LZ.

语种：英文

外文关键词：Burkholderia thailandensis MSMB43; Fermentation optimization; FK228; Genome mining; Natural product; Productivity

摘要：FK228 is an FDA-approved anticancer drug naturally produced by Chromobacterium violaceum No. 968 up to 19 mg/L in a pilot industry-scale batch fermentation. Here we report a genomics-guided discovery of Burkholderia thailandensis MSMB43 as a new and significantly better source of FK228. The genome of B. thailandensis MSMB43 was found to contain a functional biosynthetic gene cluster highly homologous to that of FK228 in C. violaceum No. 968, and the bacterium indeed produces authentic FK228. By simple fermentation in shaking flasks in a preferred M8 medium, B. thailandensis MSMB43 produced FK228 up to 67.7 mg/L; by fed-batch fermentation in a 20-L fermentor in M8 medium, B. thailandensis MSMB43 produced FK228 up to 115.9 mg/L, which is 95 fold higher than that of C. violaceum No. 968 under the same laboratory fermentation conditions. RT-PCR analysis indicated that the high FK228 yield of B. thailandensis MSMB43 was due to high expression of biosynthetic genes, represented by Bth_depA, during the fermentation process. Further genetic manipulation resulted in a recombinant strain, B. thailandensis MSMB43/pBMTL3-tdpR, which harbors a broad host-range vector expressing the thailandepsin biosynthetic pathway regulatory gene tdpR. This engineered strain produced up to 168.5 mg/L of FK228 in fed-batch fermentation in a 20-L fermentor in M8 medium. Therefore, the wild-type B. thailandensis MSMB43 or its engineered derivative could potentially be a good starting point for an industrial process to improve FK228 production for its expanding use in therapy.