Associate toxin-antitoxin with CRISPR-Cas to kill multidrug-resistant pathogens

Rui Wang, Xian Shu, Huiwei Zhao, Qiong Xue, Chao Liu, Aici Wu, Feiyue Cheng, Lingyun Wang, Yihan Zhang, Jie Feng, Nannan Wu and Ming Li ()
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Rui Wang: Chinese Academy of Sciences
Xian Shu: Chinese Academy of Sciences
Huiwei Zhao: Chinese Academy of Sciences
Qiong Xue: Chinese Academy of Sciences
Chao Liu: Chinese Academy of Sciences
Aici Wu: Chinese Academy of Sciences
Feiyue Cheng: Chinese Academy of Sciences
Lingyun Wang: Chinese Academy of Sciences
Yihan Zhang: Chinese Academy of Sciences
Jie Feng: University of Chinese Academy of Sciences
Nannan Wu: Shanghai Public Health Clinical Center, Fudan University
Ming Li: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract CreTA, CRISPR-regulated toxin-antitoxin (TA), safeguards CRISPR-Cas immune systems by inducing cell dormancy/death upon their inactivation. Here, we characterize a bacterial CreTA associating with the I-F CRISPR-Cas in Acinetobacter. CreT is a distinct bactericidal small RNA likely targeting several essential RNA molecules that are required to initiate protein synthesis. CreA guides the CRISPR effector to transcriptionally repress CreT. We further demonstrate a proof-of-concept antimicrobial strategy named ATTACK, which AssociaTes TA and CRISPR-Cas to Kill multidrug resistant (MDR) pathogens. In this design, CRISPR-Cas is programed to target antibiotic resistance gene(s) to selectively kill MDR pathogens or cure their resistance, and when CRISPR-Cas is inactivated or suppressed by unwanted genetic or non-genetic events/factors, CreTA triggers cell death as the last resort. Our data highlight the diversity of RNA toxins coevolving with CRISPR-Cas, and illuminate a combined strategy of CRISPR and TA antimicrobials to ‘ATTACK’ MDR pathogens.

Date: 2023
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DOI: 10.1038/s41467-023-37789-y

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