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Drug repurposing offers a rapid strategy to identify compounds that enhance intracellular antibacterial activity by modulating host pathways. Here, a high\u2010throughput screen of 6297 clinically approved compounds in\n                    <jats:italic>S. aureus<\/jats:italic>\n                    \u2010infected A549 cells identified 5\u2010fluoro\u20102\u2032\u2010deoxycytidine (5\u2010FdC) as an effective intracellular inhibitor. When combined with rifapentine (5FR), 5\u2010FdC displayed synergistic activity across community\u2010 and hospital\u2010acquired MRSA and MSSA strains, as well as in different host cell types, including non\u2010tumorigenic bronchial cells. Metabolomic and host RNA\u2010sequencing analyses showed that 5\u2010FdC treatment activated host stress\u2010response and DNA damage response (DDR) pathways while restoring infection\u2010induced metabolic imbalances, particularly in amino acid and central carbon metabolism. These transcriptional and metabolic changes correlated with reduced intracellular bacterial markers. In vivo, the 5FR combination significantly decreased bacterial loads in\n                    <jats:italic>Galleria mellonella<\/jats:italic>\n                    and murine pneumonia models without detectable toxicity. This study presents the largest repurposing screen performed against intracellular\n                    <jats:italic>S. aureus<\/jats:italic>\n                    and identifies a synergistic host\u2010 and pathogen\u2010targeted combination that enhances bacterial clearance through coordinated modulation of host DDR, stress, and metabolic responses.\n                  <\/jats:p>","DOI":"10.1002\/mbo3.70317","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T11:33:03Z","timestamp":1779967983000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Host\u2013Pathogen Dual Targeting With Repurposed Drugs Identifies a Synergistic Therapy for Intracellular\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1002","volume":"15","author":[{"given":"Blanca","family":"Lorente\u2010Torres","sequence":"first","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, 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