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Mycobacteriophages show exciting prospects for the treatment of drug-resistant bacterial infections. However, the molecular mechanism through which they escape host bacterial defenses remains unclear. Here, we report that the gene\n                    <jats:italic>gp48<\/jats:italic>\n                    of the mycobacteriophage A10ZJ24, which encodes a metallophosphoesterase-like protein, is essential for killing\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    . Gp48 is expressed during early stages of phage infection, and the Gp48 protein efficiently disrupts mycobacterial genomic DNA integrity, thereby silencing the expression of multiple anti-phage defense genes. While\n                    <jats:italic>gp48<\/jats:italic>\n                    -deletion phages infect and inject their DNA normally into\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    cells, they are not able to impair the activation of the bacterial anti-phage genes which inhibit the replication of the genomic DNA of the mutant phage. This study thus identifies a phage metallophosphoesterase as a novel tool for subverting host bacterial antiviral immunity and killing\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    . Our work fills a critical gap in the current knowledge on the arms race between mycobacteriophages and\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s44319-025-00488-4","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T03:08:34Z","timestamp":1748488114000},"page":"3594-3613","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A conserved phage phosphoesterase enables evasion of bacterial antiviral immunity"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1443-0940","authenticated-orcid":false,"given":"Junlong","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihao","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5307-3874","authenticated-orcid":false,"given":"Xiao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0945-4095","authenticated-orcid":false,"given":"Zheng-Guo","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"488_CR1","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1038\/s41564-022-01258-x","volume":"7","author":"BA Adler","year":"2022","unstructured":"Adler BA, Hessler T, Cress BF, Lahiri A, Mutalik VK, Barrangou R, Banfield J, Doudna JA (2022) Broad-spectrum CRISPR-Cas13a enables efficient phage genome editing. 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