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Resolving how pathogens respond to antibiotics under different contexts is critical for understanding disease emergence. It remains unclear how interactions between hosts and antibiotics impact pathogen evolution. Here, we evolved\n                    <jats:italic>Staphylococcus aureus,<\/jats:italic>\n                    a major bacterial pathogen, varying exposure to host and antibiotics to tease apart the contributions of these selective pressures on pathogen adaptation. After 12 passages,\n                    <jats:italic>S. aureus<\/jats:italic>\n                    evolving in\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    nematodes exposed to a sub-minimum inhibitory antibiotic concentration became highly virulent, regardless of whether the ancestral pathogen was methicillin-resistant (MRSA) or methicillin-sensitive (MSSA). Host and antibiotic selected for reduced drug susceptibility in MSSA while increasing MRSA total growth outside hosts. We identified mutations in genes involved in regulatory networks linking virulence and metabolism, suggesting that rapid adaptation to infect hosts may have pleiotropic effects. Mutations that arose in these genes were also enriched in clinical isolates associated with systemic infections in humans. Despite evolving in similar environments, MRSA and MSSA populations\u2014differing only in the presence of an intact accessory gene\u2014proceeded on divergent evolutionary paths, with MSSA populations exhibiting more similarities across replicates. Our results underscore the importance of the host context as a driver of virulence and antibiotic resistance.\n                  <\/jats:p>","DOI":"10.7554\/elife.107936","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T14:32:51Z","timestamp":1757428371000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.107936","source":"Crossref","is-referenced-by-count":2,"title":["Host and antibiotic jointly select for greater virulence in Staphylococcus aureus"],"prefix":"10.7554","volume":"14","author":[{"given":"Michelle","family":"Su","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03czfpz43","id-type":"ROR","asserted-by":"publisher"}],"name":"Emory University School of Medicine, Division of Infectious Diseases","place":["Atlanta, United 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