Activating natural product synthesis using CRISPR interference and activation systems in Streptomyces

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dc.citation.firstpage7751
dc.citation.issueNumber13
dc.citation.journalTitleNucleic Acids Research
dc.citation.lastpage7760
dc.citation.volumeNumber50
dc.contributor.authorAmeruoso, Andrea
dc.contributor.authorVillegas Kcam, Maria Claudia
dc.contributor.authorCohen, Katherine Piper
dc.contributor.authorChappell, James
dc.date.accessioned2022-08-04T14:53:24Z
dc.date.available2022-08-04T14:53:24Z
dc.date.issued2022
dc.description.abstractThe rise of antibiotic-resistant bacteria represents a major threat to global health, creating an urgent need to discover new antibiotics. Natural products derived from the genus Streptomyces represent a rich and diverse repertoire of chemical molecules from which new antibiotics are likely to be found. However, a major challenge is that the biosynthetic gene clusters (BGCs) responsible for natural product synthesis are often poorly expressed under laboratory culturing conditions, thus preventing the isolation and screening of novel chemicals. To address this, we describe a novel approach to activate silent BGCs through rewiring endogenous regulation using synthetic gene regulators based upon CRISPR-Cas. First, we refine CRISPR interference (CRISPRi) and create CRISPR activation (CRISPRa) systems that allow for highly programmable and effective gene repression and activation in Streptomyces. We then harness these tools to activate a silent BGC by perturbing its endogenous regulatory network. Together, this work advances the synthetic regulatory toolbox for Streptomyces and facilitates the programmable activation of silent BGCs for novel chemical discovery.
dc.identifier.citationAmeruoso, Andrea, Villegas Kcam, Maria Claudia, Cohen, Katherine Piper, et al.. "Activating natural product synthesis using CRISPR interference and activation systems in Streptomyces." <i>Nucleic Acids Research,</i> 50, no. 13 (2022) Oxford University Press: 7751-7760. https://doi.org/10.1093/nar/gkac556.
dc.identifier.digitalgkac556
dc.identifier.doihttps://doi.org/10.1093/nar/gkac556
dc.identifier.urihttps://hdl.handle.net/1911/112974
dc.language.isoeng
dc.publisherOxford University Press
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleActivating natural product synthesis using CRISPR interference and activation systems in Streptomyces
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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