Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228

Xiangyang Liu, Feng Xie, Leah B. Doughty, Qi Wang, Lixin Zhang, Xueting Liu, Yiqiang Cheng

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)268-274
Number of pages7
JournalSynthetic and Systems Biotechnology
Volume3
Issue number4
DOIs
StatePublished - 1 Dec 2018

Fingerprint

Genomics
Fermentation
Genes
Pharmaceutical Preparations
Bioreactors
Ports and harbors
Chromobacterium
Burkholderia
romidepsin
Bacteria
Host Specificity
Biosynthetic Pathways
Regulator Genes
Multigene Family
Derivatives
Industry
Genome
Gene Expression
Polymerase Chain Reaction

Keywords

  • Burkholderia thailandensis MSMB43
  • FK228
  • Fermentation optimization
  • Genome mining
  • Natural product
  • Productivity

Cite this

Liu, Xiangyang ; Xie, Feng ; Doughty, Leah B. ; Wang, Qi ; Zhang, Lixin ; Liu, Xueting ; Cheng, Yiqiang. / Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228. In: Synthetic and Systems Biotechnology. 2018 ; Vol. 3, No. 4. pp. 268-274.
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Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228. / Liu, Xiangyang; Xie, Feng; Doughty, Leah B.; Wang, Qi; Zhang, Lixin; Liu, Xueting; Cheng, Yiqiang.

In: Synthetic and Systems Biotechnology, Vol. 3, No. 4, 01.12.2018, p. 268-274.

Research output: Contribution to journalArticle

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