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With the bottleneck period of the development of new antibiotics, novel alternative agents are urgently in need. In this study, the small molecule amentoflavone is identified as a dual\u2010action inhibitor of Hla, a pore\u2010forming virulence determinant particularly important for <jats:italic>S. aureus<\/jats:italic> pathogenicity and Toll\u2010like receptor 2 (TLR2) signaling, which triggers inflammation response upon recognizing pathogen\u2010associated molecular patterns. Amentoflavone treatment conferred effective protection against <jats:italic>S. aureus<\/jats:italic> pneumonia through this dual\u2010action mechanism. Mechanically, amentoflavone effectively inhibited Hla pore formation, thereby reducing Hla\u2010mediated cytotoxicity and tissue damage; at the same time, amentoflavone suppressed TLR2\u2010mediated inflammatory response by blocking the interaction between TLR2 and its adapter myeloid differentiation primary response gene 88 (MyD88). Surprisingly, TLR2 signaling induced by synthetic bacterial TLR2 agonists and other heat\u2010killed gram\u2010positive bacteria is also blocked by amentoflavone. In summary, these results presented amentoflavone as a potential antibiotic alternative that curbed <jats:italic>S. aureus<\/jats:italic> infection by simultaneously suppressing host\u2010damaging virulence determinants derived from bacteria and the detrimental effect of excessive inflammation derived from the host rather than bacteria viability.<\/jats:p>","DOI":"10.1002\/adbi.202200109","type":"journal-article","created":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T02:25:09Z","timestamp":1656296709000},"source":"Crossref","is-referenced-by-count":2,"title":["A Dual\u2010Action Molecule Suppresses <i>S. aureus<\/i> Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling"],"prefix":"10.1002","volume":"6","author":[{"given":"Tingting","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory for Zoonotic Diseases Key Laboratory of Zoonosis Research Ministry of Education Institute of Zoonosis College of Veterinary Medicine Jilin University  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