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The objective of this study was to evaluate the antibacterial and antibiofilm activity of mocravimod (KRP-203), an FDA-approved S1P receptor modulator, against clinical\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      isolates and to explore its underlying mechanism of action. The antibacterial activity of KRP-203 was assessed against methicillin-susceptible\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      (MSSA) and methicillin-resistant\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      (MRSA) using MIC determination, time-kill assays, and biofilm inhibition models. KRP-203 exhibited strong bactericidal activity against planktonic MSSA and MRSA, with MIC values ranging 6.25\u201350\u03bcM. Time-kill assays demonstrated rapid bacterial eradication at 8\u00d7 MIC within 2 h, showing superior killing kinetics compared with vancomycin. At sub-inhibitory concentrations, KRP-203 inhibited biofilm formation by up to 70% and reduced viable bacterial counts in mature biofilms by &gt;2.5 logs. To elucidate the antibacterial mechanism, whole-genome sequencing and quantitative proteomic analyses were performed. These analyses revealed mutations in membrane-associated genes, including glnQ and BCAT, and significant alterations in proteins related to membrane integrity and redox regulation. Consistently, functional assays confirmed that KRP-203 disrupts bacterial cell membrane, as evidenced by dose-dependent membrane depolarization, increased permeability, and direct binding to cardiolipin and phosphatidylglycerol. Molecular docking further predicted a favorable interaction between KRP-203 and GlnQ. In conclusion, KRP-203 demonstrated notable antibacterial and antibiofilm activity against\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      , likely through membrane integrity disruption. While these findings highlight its potential as a repurposed antibacterial agent, further studies are required to fully elucidate its molecular targets, optimize antibacterial efficacy, and evaluate its\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      safety profile.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Antibiotic resistance and the formation of biofilms, which protect bacteria from medications and immunological responses, present the significant challenges for the clinical treatment of\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      infections. This study reveals mocravimod hydrochloride (KRP-203), a clinically approved drug initially intended to treat leukemia, as a viable new candidate against S. aureus infection. KRP-203 quickly kills both drug-susceptible and resistant\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      , including difficult-to-treat biofilm-associated cells. Its membrane-disrupting activity quickly kills drug-resistant bacteria while also destroying biofilm formations, presenting a dual action rarely accomplished by conventional antibiotics. Critically, KRP-203\u2019s established safety profile in human studies may hasten its repurposing as a new weapon against biofilm-associated infections, providing possible solutions for chronic and drug-resistant\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      infections where existing treatments commonly fail.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02263-25","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T13:05:22Z","timestamp":1785157522000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Mocravimod as a repurposing drug against clinical isolates of\n                    <i>Staphylococcus aureus<\/i>\n                    by targeting cell membrane"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2963-182X","authenticated-orcid":false,"given":"Yuanyuan","family":"Tang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03sd35x91","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University","place":["Nanjing, China"]},{"name":"Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, Shenzhen Nanshan People\u2019s Hospital, Affiliated Nanshan Hospital of Shenzhen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Xia","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03sd35x91","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University","place":["Nanjing, China"]},{"name":"Department of Infectious 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