Bacterial resistance to CRISPR-Cas antimicrobials

Abstract In the age of antibiotic resistance and precise microbiome engineering, CRISPR-Cas antimicrobials promise to have a substantial impact on the way we treat diseases in the future. However, the efficacy of these antimicrobials and their mechanisms of resistance remain to be elucidated. We sys...

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Autores principales:	Ruben V. Uribe, Christin Rathmer, Leonie Johanna Jahn, Mostafa Mostafa Hashim Ellabaan, Simone S. Li, Morten Otto Alexander Sommer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/abe1e98c25074767ad4e8e079518f630
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spelling	oai:doaj.org-article:abe1e98c25074767ad4e8e079518f6302021-12-02T18:53:19ZBacterial resistance to CRISPR-Cas antimicrobials10.1038/s41598-021-96735-42045-2322https://doaj.org/article/abe1e98c25074767ad4e8e079518f6302021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96735-4https://doaj.org/toc/2045-2322Abstract In the age of antibiotic resistance and precise microbiome engineering, CRISPR-Cas antimicrobials promise to have a substantial impact on the way we treat diseases in the future. However, the efficacy of these antimicrobials and their mechanisms of resistance remain to be elucidated. We systematically investigated how a target E. coli strain can escape killing by episomally-encoded CRISPR-Cas9 antimicrobials. Using Cas9 from Streptococcus pyogenes (SpCas9) we studied the killing efficiency and resistance mutation rate towards CRISPR-Cas9 antimicrobials and elucidated the underlying genetic alterations. We find that killing efficiency is not correlated with the number of cutting sites or the type of target. While the number of targets did not significantly affect efficiency of killing, it did reduce the emergence of chromosomal mutations conferring resistance. The most frequent target of resistance mutations was the plasmid-encoded SpCas9 that was inactivated by bacterial genome rearrangements involving translocation of mobile genetic elements such as insertion elements. This resistance mechanism can be overcome by re-introduction of an intact copy of SpCas9. The work presented here provides a guide to design strategies that reduce resistance and improve the activity of CRISPR-Cas antimicrobials.Ruben V. UribeChristin RathmerLeonie Johanna JahnMostafa Mostafa Hashim EllabaanSimone S. LiMorten Otto Alexander SommerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ruben V. Uribe Christin Rathmer Leonie Johanna Jahn Mostafa Mostafa Hashim Ellabaan Simone S. Li Morten Otto Alexander Sommer Bacterial resistance to CRISPR-Cas antimicrobials
description	Abstract In the age of antibiotic resistance and precise microbiome engineering, CRISPR-Cas antimicrobials promise to have a substantial impact on the way we treat diseases in the future. However, the efficacy of these antimicrobials and their mechanisms of resistance remain to be elucidated. We systematically investigated how a target E. coli strain can escape killing by episomally-encoded CRISPR-Cas9 antimicrobials. Using Cas9 from Streptococcus pyogenes (SpCas9) we studied the killing efficiency and resistance mutation rate towards CRISPR-Cas9 antimicrobials and elucidated the underlying genetic alterations. We find that killing efficiency is not correlated with the number of cutting sites or the type of target. While the number of targets did not significantly affect efficiency of killing, it did reduce the emergence of chromosomal mutations conferring resistance. The most frequent target of resistance mutations was the plasmid-encoded SpCas9 that was inactivated by bacterial genome rearrangements involving translocation of mobile genetic elements such as insertion elements. This resistance mechanism can be overcome by re-introduction of an intact copy of SpCas9. The work presented here provides a guide to design strategies that reduce resistance and improve the activity of CRISPR-Cas antimicrobials.
format	article
author	Ruben V. Uribe Christin Rathmer Leonie Johanna Jahn Mostafa Mostafa Hashim Ellabaan Simone S. Li Morten Otto Alexander Sommer
author_facet	Ruben V. Uribe Christin Rathmer Leonie Johanna Jahn Mostafa Mostafa Hashim Ellabaan Simone S. Li Morten Otto Alexander Sommer
author_sort	Ruben V. Uribe
title	Bacterial resistance to CRISPR-Cas antimicrobials
title_short	Bacterial resistance to CRISPR-Cas antimicrobials
title_full	Bacterial resistance to CRISPR-Cas antimicrobials
title_fullStr	Bacterial resistance to CRISPR-Cas antimicrobials
title_full_unstemmed	Bacterial resistance to CRISPR-Cas antimicrobials
title_sort	bacterial resistance to crispr-cas antimicrobials
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/abe1e98c25074767ad4e8e079518f630
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Bacterial resistance to CRISPR-Cas antimicrobials

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