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

Andrea Ameruoso, Maria Claudia Villegas Kcam, Katherine Piper Cohen, View ORCID ProfileJames Chappell
doi: https://doi.org/10.1101/2021.10.28.466254
Andrea Ameruoso
1Department of BioSciences, Rice University, 6100 Main Street, MS 140, Houston, TX 77005, USA
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Maria Claudia Villegas Kcam
1Department of BioSciences, Rice University, 6100 Main Street, MS 140, Houston, TX 77005, USA
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Katherine Piper Cohen
1Department of BioSciences, Rice University, 6100 Main Street, MS 140, Houston, TX 77005, USA
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James Chappell
1Department of BioSciences, Rice University, 6100 Main Street, MS 140, Houston, TX 77005, USA
2Department of Bioengineering, Rice University, 6100 Main Street, MS 142, Houston, TX 77005, USA
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  • ORCID record for James Chappell
  • For correspondence: jc125@rice.edu
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ABSTRACT

The 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 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 create CRISPR interference (CRISPRi) and 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 through 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted October 28, 2021.
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Activating natural product synthesis using CRISPR interference and activation systems in Streptomyces
Andrea Ameruoso, Maria Claudia Villegas Kcam, Katherine Piper Cohen, James Chappell
bioRxiv 2021.10.28.466254; doi: https://doi.org/10.1101/2021.10.28.466254
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Activating natural product synthesis using CRISPR interference and activation systems in Streptomyces
Andrea Ameruoso, Maria Claudia Villegas Kcam, Katherine Piper Cohen, James Chappell
bioRxiv 2021.10.28.466254; doi: https://doi.org/10.1101/2021.10.28.466254

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