Mechanism of Action and In Vivo Efficacy of a Human-Derived Antibody against Staphylococcus aureus α-Hemolysin
Mechanism of Action and In Vivo Efficacy of a Human-Derived Antibody against Staphylococcus aureus α-Hemolysin
复制标题
DOI：
10.1016/j.jmb.2013.02.008
复制
发表时间：
2013-05-27
影响因子：
5.6
通讯作者：
Shelton, Dave
中科院分区：
文献类型：
--
作者：
Folettit, Davide;Strop, Pavel;Shelton, Dave
多重耐药金黄色葡萄球菌菌株在医院和社区的出现和传播强调了开发新的治疗干预措施的紧迫性。我们的方法是评估利用人类免疫系统来指导新疗法开发的潜力。我们探讨了预先存在的抗链球菌抗体的作用。通过分离和表征一种对α-溶血素具有显著高亲和力的抗体，检测人个体血清中的金黄色葡萄球菌α-溶血素。该抗体在S.金黄色葡萄球菌肺炎、皮肤和菌血症小鼠感染模型，并且当在肺炎模型中给药至感染后18小时时也显示出治疗功效。此外，在肺炎和菌血症动物模型中，α-溶血素抗体的疗效似乎与抗生素利奈唑胺相加。为了更好地理解这种分离的抗体的作用机制，我们解析了α-溶血素：抗体复合物的晶体结构。据我们所知，这是首次报道的α-溶血素单体的晶体结构。复合物的结构显示抗体在帽结构域和边缘结构域之间结合α-溶血素。结合生物化学数据，结构表明抗体通过阻止与易感宿主细胞的质膜结合来中和毒素的活性。本文提供的数据表明，针对S.金黄色葡萄球菌分子存在于一些个体中，并且这种抗体单独或与抗生素组合具有治疗潜力。(C)2013爱思唯尔有限公司保留所有权利。
The emergence and spread of multi-drug-resistant strains of Staphylococcus aureus in hospitals and in the community emphasize the urgency for the development of novel therapeutic interventions. Our approach was to evaluate the potential of harnessing the human immune system to guide the development of novel therapeutics. We explored the role of preexisting antibodies against S. aureus alpha-hemolysin in the serum of human individuals by isolating and characterizing one antibody with a remarkably high affinity to alpha-hemolysin. The antibody provided protection in S. aureus pneumonia, skin, and bacteremia mouse models of infection and also showed therapeutic efficacy when dosed up to 18 h post-infection in the pneumonia model. Additionally, in pneumonia and bacteremia animal models, the therapeutic efficacy of the alpha-hemolysin antibody appeared additive to the antibiotic linezolid. To better understand the mechanism of action of this isolated antibody, we solved the crystal structure of the alpha-hemolysin:antibody complex. To our knowledge, this is the first report of the crystal structure of the alpha-hemolysin monomer. The structure of the complex shows that the antibody binds alpha-hemolysin between the cap and the rim domains. In combination with biochemical data, the structure suggests that the antibody neutralizes the activity of the toxin by preventing binding to the plasma membrane of susceptible host cells. The data presented here suggest that protective antibodies directed against S. aureus molecules exist in some individuals and that such antibodies have a therapeutic potential either alone or in combination with antibiotics. (C) 2013 Elsevier Ltd. All rights reserved.