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Acquisition of a mosaic version of the \u03a611 prophage (m\u03a611) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present study shows how prophage m\u03a611 exerts its effect on virulence for skin infection without encoding known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an m\u03a611-encoded adenine methyltransferase (designated\n                    <jats:italic>pamA<\/jats:italic>\n                    ).\n                    <jats:italic>pamA<\/jats:italic>\n                    increased expression of fibronectin-binding protein A (\n                    <jats:italic>fnbA<\/jats:italic>\n                    ; FnBPA), and inactivation of\n                    <jats:italic>fnbA<\/jats:italic>\n                    eliminated the effect of\n                    <jats:italic>pamA<\/jats:italic>\n                    on abscess virulence without affecting strains lacking\n                    <jats:italic>pamA<\/jats:italic>\n                    . Thus,\n                    <jats:italic>fnbA<\/jats:italic>\n                    is a\n                    <jats:italic>pamA<\/jats:italic>\n                    -specific virulence factor. Mechanistically,\n                    <jats:italic>pamA<\/jats:italic>\n                    was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA\u2019s role in biofilm formation. Collectively, these data reveal a critical mechanism \u2014 epigenetic regulation of staphylococcal gene expression \u2014 by which phage can regulate virulence to drive adaptive leaps by\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1172\/jci177872","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T17:16:16Z","timestamp":1753290976000},"source":"Crossref","is-referenced-by-count":10,"title":["Prophage-encoded methyltransferase drives adaptation of community-acquired methicillin-resistant Staphylococcus aureus"],"prefix":"10.1172","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3217-5062","authenticated-orcid":true,"given":"Robert J.","family":"Ulrich","sequence":"first","affiliation":[{"name":"Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Podkowik","sequence":"additional","affiliation":[{"name":"Department of Medicine and"},{"name":"Antimicrobial-Resistant Pathogens Program, New York University (NYU) Grossman School of Medicine, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Tierce","sequence":"additional","affiliation":[{"name":"Division of Comparative Medicine, NYU Langone Health, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irnov","family":"Irnov","sequence":"additional","affiliation":[{"name":"Department of Microbiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Putzel","sequence":"additional","affiliation":[{"name":"Antimicrobial-Resistant Pathogens Program, New York University (NYU) Grossman School of Medicine, New York, New York, USA."},{"name":"Department of Microbiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora M.","family":"Samhadaneh","sequence":"additional","affiliation":[{"name":"Antimicrobial-Resistant Pathogens Program, New York University (NYU) Grossman School of Medicine, New York, New York, USA."},{"name":"Department of Microbiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keenan A.","family":"Lacey","sequence":"additional","affiliation":[{"name":"Department of Microbiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiane","family":"Boff","sequence":"additional","affiliation":[{"name":"Department of Microbiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina M.","family":"Morales","sequence":"additional","affiliation":[{"name":"Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohei","family":"Makita","sequence":"additional","affiliation":[{"name":"Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodora K.","family":"Karagounis","sequence":"additional","affiliation":[{"name":"Ronald O. 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