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In situ targeted mutagenesis of gut bacteria

View ORCID ProfileAndreas K Brödel, Loïc Charpenay, Matthieu Galtier, Fabien J Fuche, View ORCID ProfileRémi Terrasse, Chloé Poquet, Marion Arraou, Gautier Prevot, Dalila Spadoni, View ORCID ProfileEdith M Hessel, View ORCID ProfileJesus Fernandez-Rodriguez, Xavier Duportet, View ORCID ProfileDavid Bikard
doi: https://doi.org/10.1101/2022.09.30.509847
Andreas K Brödel
1Eligo Bioscience, 75013 Paris, France
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  • ORCID record for Andreas K Brödel
Loïc Charpenay
1Eligo Bioscience, 75013 Paris, France
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Matthieu Galtier
1Eligo Bioscience, 75013 Paris, France
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Fabien J Fuche
1Eligo Bioscience, 75013 Paris, France
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Rémi Terrasse
1Eligo Bioscience, 75013 Paris, France
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Chloé Poquet
1Eligo Bioscience, 75013 Paris, France
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Marion Arraou
1Eligo Bioscience, 75013 Paris, France
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Gautier Prevot
1Eligo Bioscience, 75013 Paris, France
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Dalila Spadoni
1Eligo Bioscience, 75013 Paris, France
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Edith M Hessel
1Eligo Bioscience, 75013 Paris, France
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Jesus Fernandez-Rodriguez
1Eligo Bioscience, 75013 Paris, France
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  • For correspondence: david.bikard@pasteur.fr
Xavier Duportet
1Eligo Bioscience, 75013 Paris, France
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  • For correspondence: david.bikard@pasteur.fr
David Bikard
1Eligo Bioscience, 75013 Paris, France
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  • For correspondence: david.bikard@pasteur.fr
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Abstract

Microbiome research is revealing a growing number of bacterial genes that impact our health. While CRISPR-derived tools have shown great success in editing disease-driving genes in human cells, we currently lack the tools to achieve comparable success for bacterial targets. Here we engineer a phage-derived particle to deliver a base editor and modify E. coli colonizing the mouse gut. This was achieved using a non-replicative DNA payload, preventing maintenance and dissemination of the payload, while allowing for an editing efficiency of up to 99.7% of the target bacterial population. The editing of a β-lactamase gene resulted in the stable maintenance of edited bacteria in the mouse gut at least 42 days after treatment. By enabling the in situ modification of bacteria directly in the gut, our approach offers a novel avenue to investigate the function of bacterial genes and provides an opportunity to develop novel microbiome-targeted therapies.

Competing Interest Statement

All authors are current employees or paid advisors of Eligo Bioscience. Eligo Bioscience owns US patents #11,224,621 and #11,376,286, and international patent application WO2021/204967 relating to certain research described in this article.

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Posted September 30, 2022.
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In situ targeted mutagenesis of gut bacteria
Andreas K Brödel, Loïc Charpenay, Matthieu Galtier, Fabien J Fuche, Rémi Terrasse, Chloé Poquet, Marion Arraou, Gautier Prevot, Dalila Spadoni, Edith M Hessel, Jesus Fernandez-Rodriguez, Xavier Duportet, David Bikard
bioRxiv 2022.09.30.509847; doi: https://doi.org/10.1101/2022.09.30.509847
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In situ targeted mutagenesis of gut bacteria
Andreas K Brödel, Loïc Charpenay, Matthieu Galtier, Fabien J Fuche, Rémi Terrasse, Chloé Poquet, Marion Arraou, Gautier Prevot, Dalila Spadoni, Edith M Hessel, Jesus Fernandez-Rodriguez, Xavier Duportet, David Bikard
bioRxiv 2022.09.30.509847; doi: https://doi.org/10.1101/2022.09.30.509847

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