Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1783369140788002816 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6222137 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | KeAi Publishing |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT liuxiangyang genomicsguideddiscoveryofanewandsignificantlybettersourceofanticancernaturaldrugfk228 AT xiefeng genomicsguideddiscoveryofanewandsignificantlybettersourceofanticancernaturaldrugfk228 AT doughtyleahb genomicsguideddiscoveryofanewandsignificantlybettersourceofanticancernaturaldrugfk228 AT wangqi genomicsguideddiscoveryofanewandsignificantlybettersourceofanticancernaturaldrugfk228 AT zhanglixin genomicsguideddiscoveryofanewandsignificantlybettersourceofanticancernaturaldrugfk228 AT liuxueting genomicsguideddiscoveryofanewandsignificantlybettersourceofanticancernaturaldrugfk228 AT chengyiqiang genomicsguideddiscoveryofanewandsignificantlybettersourceofanticancernaturaldrugfk228 |