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<i>Staphylococcus aureus</i> （<i>S. aureus</i>）, more specifically methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), is a bacterial pathogen that poses a serious threat to human health. MRSA exhibits a high degree of resistance and multiple virulence factors, especially the formation of biofilm that increasingly complicate treatment. Therefore, it is essential to develop novel antimicrobials. Here we investigated artesunate (ART), a sesquiterpene lactone extracted from Artemisia annua, as an antivirulence agent and antimicrobial sensitizer of <i>S. aureus</i>. In this study, it was showed that ART significantly reduced biofilm formation by <i>S. aureus</i> at sub-minimal inhibitory concentrations (MICs) through the inhibition of polysaccharide intercellular adhesin (PIA) production, without affecting bacterial growth. Molecular docking indicated that the down-regulated <i>icaA</i> gene identified in qRT-PCR may be the target of ART. Moreover, evidence was brought that ART reduced hemolysin, lipase, and nuclease activities and attenuated <i>S. aureus</i> infections in <i>Galleria mellonella</i> models. Notably, checkerboard assays showed that the combination of ART with erythromycin, gentamicin, and vancomycin can exert synergistic effects on <i>S. aureus</i>. Low concentrations of ART were sufficient to sensitize erythromycin-resistant strains of <i>S. aureus</i>, such as the Newman strain. This study highlighted the antibiofilm and antivirulence potential of ART against <i>S. aureus</i>, and brought evidence that it may act as an antimicrobial sensitizer to avoid the development of multidrug-resistant bacteria. In conclusion, ART is a safe and effective antibiotic adjuvant against <i>S. aureus</i> infection.

金黄色葡萄球菌（Staphylococcus aureus，简称S. aureus），尤其是耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA），是一类严重威胁人类健康的细菌病原体。MRSA具有高度耐药性与多重毒力因子，尤其是生物被膜的形成，使得临床治疗愈发复杂。因此，开发新型抗菌制剂至关重要。本研究探究了从黄花蒿（Artemisia annua）中提取的倍半萜内酯类化合物青蒿琥酯（artesunate, ART）作为金黄色葡萄球菌抗毒力因子与抗菌增敏剂的应用潜力。实验结果显示，在亚最低抑菌浓度（sub-minimal inhibitory concentrations, MICs）下，ART可通过抑制多糖细胞间黏附素（polysaccharide intercellular adhesin, PIA）的产生，显著降低金黄色葡萄球菌的生物被膜形成能力，且不会影响细菌的正常生长。分子对接分析表明，定量实时聚合酶链反应（qRT-PCR）检测到的下调表达icaA基因，可能是ART的作用靶点。此外，实验证实ART可降低溶血素、脂肪酶与核酸酶的活性，并在大蜡螟（Galleria mellonella）感染模型中减弱金黄色葡萄球菌的致病力。值得注意的是，棋盘格药敏试验（checkerboard assays）结果显示，ART与红霉素（erythromycin）、庆大霉素（gentamicin）及万古霉素（vancomycin）联合使用时，对金黄色葡萄球菌可发挥协同抗菌作用。低浓度的ART即可有效增敏耐红霉素的金黄色葡萄球菌菌株，例如纽曼菌株（Newman strain）。本研究揭示了ART抗金黄色葡萄球菌生物被膜与毒力的潜在应用价值，并证实其可作为抗菌增敏剂，助力延缓多重耐药细菌的产生。综上，ART是一类安全有效的抗金黄色葡萄球菌感染抗菌佐剂。