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In this study, we employed transposon-directed insertion site sequencing (TraDIS) to map the fitness landscape of CA-MRSA strain USA300 JE2 through a genome-wide screening in fresh, immunocompetent human blood. We identified 76 genes required for fitness, including genes involved in respiratory and central carbon metabolisms, heme detoxification, and\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      purine biosynthesis. As validation of fitness genes, competition assays confirmed that individual disruption of\n                      <jats:italic toggle=\"yes\">purA<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">purB<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">fbp<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">hssR<\/jats:italic>\n                      , or\n                      <jats:italic toggle=\"yes\">aroA2<\/jats:italic>\n                      significantly reduced bacterial fitness in blood. Conversely, inactivation of specific regulators, such as the\n                      <jats:italic toggle=\"yes\">saeRS<\/jats:italic>\n                      two-component system, the alternative sigma factor \u03c3\n                      <jats:sup>B<\/jats:sup>\n                      , and adhesins, including\n                      <jats:italic toggle=\"yes\">fnbA<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">clfA<\/jats:italic>\n                      , conferred a competitive advantage. These findings provide a genome-scale map of\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      fitness requirements in a physiologically relevant blood model, offering a platform for further investigation of bacterial adaptation to the intravascular environment.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Understanding how\n                        <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                        maintains fitness in the human bloodstream is essential for explaining its success as an invasive pathogen. This study provides a comprehensive, genome-wide definition of the genes that enable\n                        <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                        to remain competitive in blood, revealing the key physiological requirements for adaptation to this challenging environment. By identifying genetic functions whose disruption impairs fitness, our findings highlight the specific pathways that sustain adaptation and competitiveness under host-imposed stress. Extending previous genome-scale investigations conducted in other infection niches, this study emphasizes the importance of physiological context in shaping bacterial fitness and identifies conserved cross-fitness determinants shared among\n                        <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                        lineages. These insights advance our current understanding of how\n                        <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                        adapts to the bloodstream and strengthen the foundation for future functional and comparative studies on staphylococcal pathophysiology.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.03585-25","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T13:06:31Z","timestamp":1776776791000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Profiling of genetic determinants required for fitness of community-associated methicillin-resistant\n                    <i>Staphylococcus aureus<\/i>\n                    in human blood"],"prefix":"10.1128","volume":"14","author":[{"given":"Nader","family":"Abdelmalek","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01bnjbv91","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical Sciences, University of Sassari","place":["Sassari, Italy"]},{"name":"Unit of Microbiology and Virology, University Hospital of Sassari","place":["Sassari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9346-8326","authenticated-orcid":false,"given":"Sally W.","family":"Yousief","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01bnjbv91","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical Sciences, University of Sassari","place":["Sassari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin 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