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In this study, a library of multi\u2010halogenated indoles was evaluated for antibacterial, antibiofilm and antivirulence activities against\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>S. aureus<\/jats:italic>\n                    <\/jats:styled-content>\n                    including methicillin\u2010resistant strains. Two lead compounds, 6\u2010bromo\u20104\u2010iodoindole and 4\u2010bromo\u20106\u2010chloroindole, exhibited potent bactericidal activity (MIC\u2009=\u200920\u201330\u2009\u03bcg\/mL) comparable to the antibiotic gentamicin, effectively inhibited biofilm formation and persister formation and suppressed key virulence haemolysis. These effects were associated with intracellular ROS generation and transcriptional downregulation of quorum\u2010sensing genes of\n                    <jats:italic>agrA<\/jats:italic>\n                    and\n                    <jats:italic>RNAIII<\/jats:italic>\n                    and virulence genes of\n                    <jats:italic>hla<\/jats:italic>\n                    and\n                    <jats:italic>nuc1<\/jats:italic>\n                    . Also, 6\u2010bromo\u20104\u2010iodoindole synergised with aminoglycoside tobramycin and gentamicin, significantly reducing their effective MICs. Notably, these two multi\u2010halogenated indoles did not induce drug resistance for 20\u2009days while gentamicin rapidly increased drug resistance. Cytotoxicity assays in HepG2 cells and phytotoxicity tests confirmed a favourable safety profile. Structure\u2013activity relationship identified multi\u2010halogenation at the C4, C5, C6 and C7 positions of indole as favourable for enhanced activities and also suggested that more halogens could improve the activities. This study highlights multi\u2010halogenated indoles as promising multi\u2010target antimicrobial agents with potential therapeutic and environmental applications against\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>S. aureus<\/jats:italic>\n                    <\/jats:styled-content>\n                    , including drug\u2010resistant and biofilm\u2010forming strains.\n                  <\/jats:p>","DOI":"10.1111\/1751-7915.70280","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T16:44:09Z","timestamp":1764780249000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Multi\u2010Halogenated Indoles as Antimicrobial and Antivirulence Agents Against Drug\u2010Resistant\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1111","volume":"18","author":[{"given":"MinHwi","family":"Sim","sequence":"first","affiliation":[{"name":"School of Chemical Engineering Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharath Reddy","family":"Boya","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong\u2010Guy","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6397-4342","authenticated-orcid":false,"given":"Jin\u2010Hyung","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering Yeungnam University  Gyeongsan Republic of 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