Background: MRSA is a major concern in community settings and in healthcare, the emergence of biofilms and persister cells formation substantially increases the antimicrobial resistance of MRSA strains. It is very urgent to develop new antimicrobials to solve this problem.Objective: Idarubicin was profiled to assess its antimicrobial effects in vitro and in vivo, as well as the underlying mechanisms.Methods: We investigated the antimicrobial effects of idarubicin against MRSA by time-kill analysis. The antibiofilm efficacy of idarubicin was assessed by crystal violet and XTT staining, followed by laser confocal microscopy observation. The mechanisms underlying the antimicrobial effects of idarubicin were studied by transmission electron microscopy, all-atom molecular dynamics simulations, SYTOX staining, surface plasma resonance, and DNA gyrase inhibition assay. In further in vivo studies, we addressed the antimicrobial efficacy in wound and subcutaneous abscess infection models.Results: Idarubicin kills both growing and persister MRSA cells by disrupting the lipid bilayers and interrupting the DNA topoisomerase IIA subunits, and idarubicin shows synergistic antimicrobial effects with fosfomycin. Through synergy with a single dose treatment fosfomycin and the addition of the cell protector amifostine, the cytotoxicity and cardiotoxicity of idarubicin were significantly reduced without affecting its antimicrobial effects in vivo. Idarubicin alone or in combination with fosfomycin exhibited considerable efficacy in a subcutaneous abscess mouse model of MRSA infection. In addition, idarubicin also showed a low probability of causing resistance and good postantibiotic effects.Conclusions: Idarubicin and its analogues have the potential to become a new class of antimicrobials for the treatment of MRSA related infections.

中文翻译：

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深入了解伊达比星对耐甲氧西林金黄色葡萄球菌的抗菌活性。

背景：MRSA是社区环境和医疗保健中的主要问题，生物膜的形成和持久性细胞的形成大大增加了MRSA菌株的抗药性。迫切需要开发出新的抗菌药物来解决这个问题。目的：对依达比星进行了体外和体内抗菌作用及其潜在作用机理的研究。方法：我们通过时间研究了伊达比星对MRSA的抗菌作用。杀死分析。通过结晶紫和XTT染色，然后通过激光共聚焦显微镜观察来评估伊达比星的抗生物膜功效。通过透射电子显微镜，全原子分子动力学模拟，SYTOX染色，表面等离子共振研究了伊达比星抗菌作用的潜在机制。和DNA旋转酶抑制试验。在进一步的体内研究中，我们研究了在伤口和皮下脓肿感染模型中的抗菌功效。结果：伊达比星通过破坏脂质双层并破坏DNA拓扑异构酶IIA亚基来杀死生长中的MRSA细胞和持久性MRSA细胞，伊达比星显示与磷霉素具有协同抗菌作用。 。通过与单剂量磷霉素的协同作用和添加细胞保护剂氨磷汀，可显着降低伊达比星的细胞毒性和心脏毒性，而不会影响其体内的抗菌作用。依达比星单独或与磷霉素合用在MRSA感染的皮下脓肿小鼠模型中显示出相当大的功效。此外，伊达比星还显示出引起耐药的可能性较低，并具有良好的抗生素后作用。