Kuo David, Yu Guanping, Hoch Wyatt, Gabay Dean, Long Lisa, Ghannoum Mahmoud, Nagy Nancy, Harding Clifford V, Viswanathan Rajesh, Shoham Menachem
Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
Center for Medical Mycology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA.
Antimicrob Agents Chemother. 2015 Mar;59(3):1512-8. doi: 10.1128/AAC.04767-14. Epub 2014 Dec 22.
The dwindling repertoire of antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) calls for novel treatment options. Quorum-quenching agents offer an alternative or an adjuvant to antibiotic therapy. Three biaryl hydroxyketone compounds discovered previously (F1, F12, and F19; G. Yu, D. Kuo, M. Shoham, and R. Viswanathan, ACS Comb Sci 16:85-91, 2014) were tested for efficacy in MRSA-infected animal models. Topical therapy of compounds F1 and F12 in a MRSA murine wound infection model promotes wound healing compared to the untreated control. Compounds F1, F12, and F19 afford significant survival benefits in a MRSA insect larva model. Combination therapy of these quorum-quenching agents with cephalothin or nafcillin, antibiotics to which MRSA is resistant in monotherapy, revealed additional survival benefits. The quorum-quenching agents sensitize MRSA to the antibiotic by a synergistic mode of action that also is observed in vitro. An adjuvant of 1 μg/ml F1, F12, or F19 reduces the MIC of nafcillin and cephalothin about 50-fold to values comparable to those for vancomycin, the antibiotic often prescribed for MRSA infections. These findings suggest that it is possible to resurrect obsolete antibiotic therapies in combination with these novel quorum-quenching agents.
用于治疗耐甲氧西林金黄色葡萄球菌（MRSA）的抗生素种类日益减少，这就需要新的治疗方案。群体感应淬灭剂为抗生素治疗提供了一种替代方案或辅助手段。对之前发现的三种联芳基羟酮化合物（F1、F12和F19；G. Yu、D. Kuo、M. Shoham和R. Viswanathan，《美国化学会组合化学杂志》16:85 - 91，2014年）在MRSA感染动物模型中的疗效进行了测试。与未治疗的对照组相比，在MRSA小鼠伤口感染模型中局部应用化合物F1和F12可促进伤口愈合。在MRSA昆虫幼虫模型中，化合物F1、F12和F19具有显著的生存益处。这些群体感应淬灭剂与头孢噻吩或萘夫西林（MRSA对其单药治疗耐药的抗生素）联合治疗显示出额外的生存益处。群体感应淬灭剂通过一种在体外也能观察到的协同作用模式使MRSA对该抗生素敏感。1μg/ml的F1、F12或F19作为佐剂可将萘夫西林和头孢噻吩的最低抑菌浓度降低约50倍，降至与通常用于治疗MRSA感染的抗生素万古霉素相当的值。这些发现表明，将这些新型群体感应淬灭剂与过时的抗生素疗法联合使用有可能重振疗效。
