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Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228.
- Source :
-
Synthetic and systems biotechnology [Synth Syst Biotechnol] 2018 Nov 05; Vol. 3 (4), pp. 268-274. Date of Electronic Publication: 2018 Nov 05 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 2405-805X
- Volume :
- 3
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Synthetic and systems biotechnology
- Publication Type :
- Academic Journal
- Accession number :
- 30417143
- Full Text :
- https://doi.org/10.1016/j.synbio.2018.10.011