Exploring novel antimicrobial drugs and strategies has become essential to the fight MRSA-associated infections. Herein, we found that membrane-disrupted repurposed antibiotic salifungin had excellent bactericidal activity against MRSA, with limited development of drug resistance. Furthermore, adding salifungin effectively decreased the minimum inhibitory concentrations of clinical antibiotics against Staphylococcus aureus. Evaluations of the mechanism demonstrated that salifungin disrupted the level of H⁺ and K⁺ ions using hydrophilic and lipophilic groups to interact with bacterial membranes, causing the disruption of bacterial proton motive force followed by impacting on bacterial the function of the respiratory chain and adenosine 5′-triphosphate, thereby inhibiting phosphatidic acid biosynthesis. Moreover, salifungin also significantly inhibited the formation of bacterial biofilms and eliminated established bacterial biofilms by interfering with bacterial membrane potential and inhibiting biofilm-associated gene expression, which was even better than clinical antibiotics. Finally, salifungin exhibited efficacy comparable to or even better than that of vancomycin in the MRSA-infected animal models. In conclusion, these results indicate that salifungin can be a potential drug for treating MRSA-associated infections.

中文翻译：

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发现沙利芬净作为一种针对耐甲氧西林金黄色葡萄球菌的新用途抗生素，且耐药性发展有限

探索新型抗菌药物和策略对于对抗 MRSA 相关感染至关重要。在此，我们发现膜破坏的重新利用的抗生素 salifungin 对 MRSA 具有优异的杀菌活性，且耐药性的发展有限。此外，添加沙利芬净有效降低了临床抗生素对金黄色葡萄球菌的最低抑菌浓度。机制评估表明，salifungin 利用亲水和亲脂基团与细菌膜相互作用，破坏 H ⁺和 K ⁺离子水平，导致细菌质子动力破坏，进而影响细菌呼吸链和腺苷 5 的功能'-三磷酸，从而抑制磷脂酸的生物合成。而且，沙利芬净还通过干扰细菌膜电位和抑制生物膜相关基因表达，显着抑制细菌生物膜的形成并消除已形成的细菌生物膜，效果甚至优于临床抗生素。最后，沙利芬净在 MRSA 感染的动物模型中表现出与万古霉素相当甚至更好的疗效。总之，这些结果表明 Salifungin 可以成为治疗 MRSA 相关感染的潜在药物。