Staphylococcus aureus can cause a variety of infections, including persistent biofilm infections, which are difficult to eradicate with current antibiotic treatments. Here, we demonstrate that combining drugs that have robust anti-persister activity, such as clinafloxacin or oritavancin, in combination with drugs that have high activity against growing bacteria, such as vancomycin or meropenem, could completely eradicate S. aureus biofilm bacteria in vitro. In contrast, single or two drugs, including the current treatment doxycycline plus rifampin for persistent S. aureus infection, failed to kill all biofilm bacteria in vitro. In a chronic persistent skin infection mouse model, we showed that the drug combination clinafloxacin + meropenem + daptomycin which killed all biofilm bacteria in vitro completely eradicated S. aureus biofilm infection in mice while the current treatments failed to do so. The complete eradication of biofilm bacteria is attributed to the unique high anti-persister activity of clinafloxacin, which could not be replaced by other fluoroquinolones including moxifloxacin, levofloxacin, or ciprofloxacin. We also compared our persister drug combination with the current approaches for treating persistent infections, including gentamicin + fructose and ADEP4 + rifampin in the S. aureus biofilm infection mouse model, and found neither treatment could eradicate the biofilm infection. Our study demonstrates an important treatment principle, the Yin–Yang model, for persistent infections by targeting both growing and non-growing heterogeneous bacterial populations, utilizing persister drugs for the more effective eradication of persistent and biofilm infections. Our findings have implications for the improved treatment of other persistent and biofilm infections in general.

中文翻译：

---

通过 Persister 药物组合根除金黄色葡萄球菌生物膜感染


金黄色葡萄球菌可引起多种感染，包括持续性生物膜感染，目前的抗生素治疗难以根除。在这里，我们证明，将具有强大抗持久活性的药物（例如克林沙星或奥利万星）与对生长细菌具有高活性的药物（例如万古霉素或美罗培南）相结合，可以在体外完全根除金黄色葡萄球菌生物膜细菌。相比之下，单一或两种药物，包括目前治疗持续性金黄色葡萄球菌感染的多西环素加利福平，未能在体外杀死所有生物膜细菌。在慢性持续性皮肤感染小鼠模型中，我们发现克林沙星+美罗培南+达托霉素的药物组合可在体外杀死所有生物膜细菌，从而完全根除小鼠体内的金黄色葡萄球菌生物膜感染，而目前的治疗方法无法做到这一点。生物膜细菌的彻底根除归功于克那沙星独特的高抗持久活性，这是其他氟喹诺酮类药物（包括莫西沙星、左氧氟沙星或环丙沙星）无法替代的。我们还将我们的持久性药物组合与当前治疗持续性感染的方法进行了比较，包括金黄色葡萄球菌生物膜感染小鼠模型中的庆大霉素+果糖和ADEP4+利福平，发现两种治疗方法都不能根除生物膜感染。我们的研究证明了一种重要的治疗原则，即阴阳模型，通过针对生长和非生长的异质细菌群体，利用持久性药物更有效地根除持续性感染和生物膜感染，来治疗持续性感染。 我们的研究结果对于改善其他持续性感染和生物膜感染的治疗具有重要意义。