This study presents a structure-guided discovery of anti-CRISPR (Acr) and anti-phage defense proteins in bacteria. By analyzing over 66 million viral protein sequences and 330,000 metagenome-assembled genomes, the researchers identified new Acr proteins and anti-phage defense systems using protein structural similarity and gene co-occurrence analyses. They predicted structures for ~300,000 proteins and performed large-scale pairwise comparisons to known Acr and anti-phage proteins to identify structural homologs. This approach enabled the discovery of a Bacteroidota phage Acr protein that inhibits Cas12a and an Akkermansia muciniphila anti-phage defense protein, termed BxaP. BxaP is found in loci encoding Bacteriophage Exclusion (BREX) and restriction-modification defense systems but confers immunity independently. The study highlights the advantage of combining protein structural features and gene co-localization information in studying host-phage interactions. Bacteriophages are the most abundant viruses on Earth and infect nearly half of all sequenced bacterial genomes. They are a significant threat to bacteria populations and can cause up to 40% of lysis in habitats such as oceans. Bacteria and phages are locked in a perpetual evolutionary warfare that has led to multiple defense and counter-defense measures. In bacteria, the most common anti-phage defense mechanisms include adaptive immune systems conferred by RNA-guided CRISPR-Cas, abortive infection (Abi) and toxin-antitoxin (TA) systems, and innate systems such as restriction-modification (RM) and cell-surface modification. Phages have evolved several mechanisms to circumvent host defenses such as anti-RM and anti-CRISPRs (Acr) proteins. Acr's are the best studied anti-defense systems and were originally discovered in 2013 from phage genomes infecting strains of Pseudomonas aeruginosa. Since then, over 100 Acr's inhibiting a wide diversity of CRISPR types have been discovered from both phages and mobile genetic elements. Acr's typically inactivate CRISPR systems by directly interacting with Cas proteins to prevent DNA cleavage or target DNA binding. In addition, some Acr's possess enzymatic activities to modify Cas proteins post-translationally. The study highlights the importance of identifying anti-phage defense and counter-defense systems in understanding the "arms race" between phages and their host. This knowledge can provide translational insights for modern therapeutics, such as precise regulation of the CRISPR system in genome editing and phage therapy. The researchers identified a Bacteroidota phage Acr protein that inhibits Cas12a and an Akkermansia muciniphila anti-phage defense protein, BxaP. BxaP is foundThis study presents a structure-guided discovery of anti-CRISPR (Acr) and anti-phage defense proteins in bacteria. By analyzing over 66 million viral protein sequences and 330,000 metagenome-assembled genomes, the researchers identified new Acr proteins and anti-phage defense systems using protein structural similarity and gene co-occurrence analyses. They predicted structures for ~300,000 proteins and performed large-scale pairwise comparisons to known Acr and anti-phage proteins to identify structural homologs. This approach enabled the discovery of a Bacteroidota phage Acr protein that inhibits Cas12a and an Akkermansia muciniphila anti-phage defense protein, termed BxaP. BxaP is found in loci encoding Bacteriophage Exclusion (BREX) and restriction-modification defense systems but confers immunity independently. The study highlights the advantage of combining protein structural features and gene co-localization information in studying host-phage interactions. Bacteriophages are the most abundant viruses on Earth and infect nearly half of all sequenced bacterial genomes. They are a significant threat to bacteria populations and can cause up to 40% of lysis in habitats such as oceans. Bacteria and phages are locked in a perpetual evolutionary warfare that has led to multiple defense and counter-defense measures. In bacteria, the most common anti-phage defense mechanisms include adaptive immune systems conferred by RNA-guided CRISPR-Cas, abortive infection (Abi) and toxin-antitoxin (TA) systems, and innate systems such as restriction-modification (RM) and cell-surface modification. Phages have evolved several mechanisms to circumvent host defenses such as anti-RM and anti-CRISPRs (Acr) proteins. Acr's are the best studied anti-defense systems and were originally discovered in 2013 from phage genomes infecting strains of Pseudomonas aeruginosa. Since then, over 100 Acr's inhibiting a wide diversity of CRISPR types have been discovered from both phages and mobile genetic elements. Acr's typically inactivate CRISPR systems by directly interacting with Cas proteins to prevent DNA cleavage or target DNA binding. In addition, some Acr's possess enzymatic activities to modify Cas proteins post-translationally. The study highlights the importance of identifying anti-phage defense and counter-defense systems in understanding the "arms race" between phages and their host. This knowledge can provide translational insights for modern therapeutics, such as precise regulation of the CRISPR system in genome editing and phage therapy. The researchers identified a Bacteroidota phage Acr protein that inhibits Cas12a and an Akkermansia muciniphila anti-phage defense protein, BxaP. BxaP is found