Yee Rebecca, Yuan Yuting, Tarff Andreina, Brayton Cory, Gour Naina, Feng Jie, Zhang Ying
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Department of Graduate Medical Education, Louis A. Weiss Memorial Hospital, Chicago, IL 60640, USA.
Antibiotics (Basel). 2022 Sep 20;11(10):1278. doi: 10.3390/antibiotics11101278.
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 biofilm bacteria in vitro. In contrast, single or two drugs, including the current treatment doxycycline plus rifampin for persistent 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 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 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.
可引发多种感染，包括持续性生物膜感染，而目前的抗生素治疗难以根除这类感染。在此，我们证明，将具有强大抗持留菌活性的药物（如克林沙星或奥利万星）与对生长细菌具有高活性的药物（如万古霉素或美罗培南）联合使用，可在体外完全根除生物膜细菌。相比之下，单一药物或两种药物（包括目前用于持续性感染治疗的强力霉素加利福平）在体外无法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，在体外能杀死所有生物膜细菌的克林沙星 + 美罗培南 + 达托霉素联合用药可在小鼠体内完全根除生物膜感染，而目前的治疗方法则无法做到。生物膜细菌的完全根除归因于克林沙星独特的高抗持留菌活性，这种活性无法被包括莫西沙星、左氧氟沙星或环丙沙星在内的其他氟喹诺酮类药物所取代。我们还在生物膜感染小鼠模型中将我们的持留菌药物联合用药与目前治疗持续性感染的方法（包括庆大霉素 + 果糖和ADEP4 + 利福平）进行了比较，发现这两种治疗方法均无法根除生物膜感染。我们的研究证明了一种重要的治疗原则——阴阳模型，即通过针对生长和非生长的异质细菌群体来治疗持续性感染，利用持留菌药物更有效地根除持续性感染和生物膜感染。我们的研究结果总体上对改善其他持续性和生物膜感染的治疗具有重要意义。
