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Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds
The formicamycins are promising antibiotics first identified in Streptomyces formicae KY5, which produces the compounds at low levels. Here, we show that by understanding the regulation of the for biosynthetic gene cluster (BGC), we can rewire the BGC to increase production levels. The for BGC consi...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062789/ https://www.ncbi.nlm.nih.gov/pubmed/33440167 http://dx.doi.org/10.1016/j.chembiol.2020.12.011 |
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author | Devine, Rebecca McDonald, Hannah P. Qin, Zhiwei Arnold, Corinne J. Noble, Katie Chandra, Govind Wilkinson, Barrie Hutchings, Matthew I. |
author_facet | Devine, Rebecca McDonald, Hannah P. Qin, Zhiwei Arnold, Corinne J. Noble, Katie Chandra, Govind Wilkinson, Barrie Hutchings, Matthew I. |
author_sort | Devine, Rebecca |
collection | PubMed |
description | The formicamycins are promising antibiotics first identified in Streptomyces formicae KY5, which produces the compounds at low levels. Here, we show that by understanding the regulation of the for biosynthetic gene cluster (BGC), we can rewire the BGC to increase production levels. The for BGC consists of 24 genes expressed on nine transcripts. The MarR regulator ForJ represses expression of seven transcripts encoding the major biosynthetic genes as well as the ForGF two-component system that initiates biosynthesis. We show that overexpression of forGF in a ΔforJ background increases formicamycin production 10-fold compared with the wild-type. De-repression, by deleting forJ, also switches on biosynthesis in liquid culture and induces the production of additional, previously unreported formicamycin congeners. Furthermore, combining de-repression with mutations in biosynthetic genes leads to biosynthesis of additional bioactive precursors. |
format | Online Article Text |
id | pubmed-8062789 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-80627892021-04-27 Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds Devine, Rebecca McDonald, Hannah P. Qin, Zhiwei Arnold, Corinne J. Noble, Katie Chandra, Govind Wilkinson, Barrie Hutchings, Matthew I. Cell Chem Biol Article The formicamycins are promising antibiotics first identified in Streptomyces formicae KY5, which produces the compounds at low levels. Here, we show that by understanding the regulation of the for biosynthetic gene cluster (BGC), we can rewire the BGC to increase production levels. The for BGC consists of 24 genes expressed on nine transcripts. The MarR regulator ForJ represses expression of seven transcripts encoding the major biosynthetic genes as well as the ForGF two-component system that initiates biosynthesis. We show that overexpression of forGF in a ΔforJ background increases formicamycin production 10-fold compared with the wild-type. De-repression, by deleting forJ, also switches on biosynthesis in liquid culture and induces the production of additional, previously unreported formicamycin congeners. Furthermore, combining de-repression with mutations in biosynthetic genes leads to biosynthesis of additional bioactive precursors. Cell Press 2021-04-15 /pmc/articles/PMC8062789/ /pubmed/33440167 http://dx.doi.org/10.1016/j.chembiol.2020.12.011 Text en © 2020 The Authors https://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 Devine, Rebecca McDonald, Hannah P. Qin, Zhiwei Arnold, Corinne J. Noble, Katie Chandra, Govind Wilkinson, Barrie Hutchings, Matthew I. Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds |
title | Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds |
title_full | Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds |
title_fullStr | Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds |
title_full_unstemmed | Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds |
title_short | Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds |
title_sort | re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062789/ https://www.ncbi.nlm.nih.gov/pubmed/33440167 http://dx.doi.org/10.1016/j.chembiol.2020.12.011 |
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