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

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 o...

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Autores principales: Liu, Xiangyang, Xie, Feng, Doughty, Leah B., Wang, Qi, Zhang, Lixin, Liu, Xueting, Cheng, Yi-Qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: KeAi Publishing 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222137/
https://www.ncbi.nlm.nih.gov/pubmed/30417143
http://dx.doi.org/10.1016/j.synbio.2018.10.011
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author Liu, Xiangyang
Xie, Feng
Doughty, Leah B.
Wang, Qi
Zhang, Lixin
Liu, Xueting
Cheng, Yi-Qiang
author_facet Liu, Xiangyang
Xie, Feng
Doughty, Leah B.
Wang, Qi
Zhang, Lixin
Liu, Xueting
Cheng, Yi-Qiang
author_sort Liu, Xiangyang
collection PubMed
description 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.
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spelling pubmed-62221372018-11-09 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, Yi-Qiang Synth Syst Biotechnol Article 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. KeAi Publishing 2018-11-05 /pmc/articles/PMC6222137/ /pubmed/30417143 http://dx.doi.org/10.1016/j.synbio.2018.10.011 Text en © 2018 Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Liu, Xiangyang
Xie, Feng
Doughty, Leah B.
Wang, Qi
Zhang, Lixin
Liu, Xueting
Cheng, Yi-Qiang
Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228
title Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228
title_full Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228
title_fullStr Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228
title_full_unstemmed Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228
title_short Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228
title_sort genomics-guided discovery of a new and significantly better source of anticancer natural drug fk228
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222137/
https://www.ncbi.nlm.nih.gov/pubmed/30417143
http://dx.doi.org/10.1016/j.synbio.2018.10.011
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