{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T05:07:48Z","timestamp":1778476068792,"version":"3.51.4"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFC2309300"],"award-info":[{"award-number":["2024YFC2309300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2023-I2M-2-006; 2021-I2M-1-039"],"award-info":[{"award-number":["2023-I2M-2-006; 2021-I2M-1-039"]}]},{"name":"National Science and Technology Infrastructure of China","award":["NPRC-32"],"award-info":[{"award-number":["NPRC-32"]}]},{"name":"Medical Research Project of Chengdu","award":["2025033"],"award-info":[{"award-number":["2025033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Staphylococcus aureus remains a leading cause of morbidity and mortality worldwide, with persistent and relapsing infections posing a major global health threat. Here, we report that baloxavir, an FDA-approved influenza antiviral, exhibits antibacterial activity against S. aureus. Baloxavir demonstrated potent activity against both MSSA and MRSA clinical isolates with MICs of 2\u20134 \u03bcg\/mL and exhibited concentration-dependent antibacterial activity in time-kill assays. Notably, baloxavir effectively eliminated intracellular S. aureus in both A549 alveolar epithelial cells and RAW264.7 macrophages at 10 \u03bcg\/mL and achieved complete eradication in A549 cells at 50 \u03bcg\/mL. In vivo, baloxavir (20\u201340 mg\/kg) significantly improved survival in MRSA-infected mice from 12.5% to 75\u201387.5%. Transcriptomic analysis revealed significant downregulation of purine de novo biosynthesis genes, including purF and purK, which was validated by RT-qPCR (r = 0.862, p = 0.027). This study demonstrates for the first time that baloxavir possesses significant antibacterial activity against S. aureus including MRSA, positioning it as a promising repurposed candidate for treating persistent intracellular infections and post-viral superinfections.<\/jats:p>","DOI":"10.3390\/ijms27093880","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:33:37Z","timestamp":1777376017000},"page":"3880","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Baloxavir Exhibits Antibacterial Activity Against Staphylococcus aureus by Inhibiting De Novo Purine Biosynthesis"],"prefix":"10.3390","volume":"27","author":[{"given":"Xue","family":"Li","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"},{"name":"Division for Medicinal Microorganisms-Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China"},{"name":"Hebei Key Laboratory of Pathogenic Mechanisms and Diagnosis & Treatment Technologies for Lung Microbiome, Zhangjiakou 075000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Yang","sequence":"additional","affiliation":[{"name":"Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People\u2019s Hospital of Chengdu, Chengdu 610031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Penghe","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"},{"name":"Division for Medicinal Microorganisms-Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tongying","family":"Nie","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"},{"name":"Division for Medicinal Microorganisms-Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinxin","family":"Hu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"},{"name":"Division for Medicinal Microorganisms-Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China"},{"name":"Hebei Key Laboratory of Pathogenic Mechanisms and Diagnosis & Treatment Technologies for Lung Microbiome, Zhangjiakou 075000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2156-1408","authenticated-orcid":false,"given":"Xuefu","family":"You","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"},{"name":"Division for Medicinal Microorganisms-Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China"},{"name":"Hebei Key Laboratory of Pathogenic Mechanisms and Diagnosis & Treatment Technologies for Lung Microbiome, Zhangjiakou 075000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiukun","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"},{"name":"Division for Medicinal Microorganisms-Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China"},{"name":"Hebei Key Laboratory of Pathogenic Mechanisms and Diagnosis & Treatment Technologies for Lung Microbiome, Zhangjiakou 075000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congran","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"},{"name":"Division for Medicinal Microorganisms-Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China"},{"name":"Hebei Key Laboratory of Pathogenic Mechanisms and Diagnosis & Treatment Technologies for Lung Microbiome, Zhangjiakou 075000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/S0140-6736(24)01867-1","article-title":"Global Burden of Bacterial Antimicrobial Resistance 1990\u20132021: A Systematic Analysis with Forecasts to 2050","volume":"404","author":"Naghavi","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1086\/591708","article-title":"Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic 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