Pseudomonas aeruginosa typically carries type I-F CRISPR-Cas systems, which are targeted by diverse (pro)phage-encoded anti-CRISPR (Acr) proteins. Here, we show that ~26% of P. aeruginosa Cas effectors are reprogrammed by a regulatory RNA guide (CreA) to transcriptionally silence a conserved small RNA toxin (CreT) that arrests cell growth upon Cas inactivation. This toxin unprecedentedly employs two consecutive proline codons, thus termed "proline-codon toxin". Combined phylogenetic and genetic analyses unraveled that CreTA has forced P. aeruginosa to reject prophages whose Acrs disrupt Cas-DNA binding, which is essential for CreT repression. We further show that Acr-armed lytic phages designed to overcome CRISPR adaptive immunity can be instead aborted by CreTA-mediated defense in vitro and in a mouse model. Our findings unravel intra-genomic arms races between CreTAs and anti-CRISPR phages, and underscore the necessity of rational engineering of strain-specific therapeutic phages to penetrate the layered CRISPR and TA barriers of multidrug-resistant P. aeruginosa.
Wang, R., Liu, C., Li, P., Xu, J., Liang, G., Wu, Y., Jiang, X., Zhao, R., Pinilla-Redondo, R., Le, S., luan, g., Li, M.
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