In vivo Testing of S. aureus alpha-Hemolysin Inhibitors

描述(申请人提供)：我们最近证明了金黄色葡萄球菌产生的α-溶血素在金黄色葡萄球菌肺炎的发病机制中起着关键作用，并确定了能有效抑制这种分泌的细菌毒素的细胞毒性作用的β-环糊精衍生物。这项可行性研究的总体目标是检验这些抑制剂在金黄色葡萄球菌肺炎小鼠模型中提供体内保护的能力。这项第一阶段研究的具体目标是：(1)建立和验证生物样品中环糊精的分析方法。(2)评价化合物的毒性和初步药代动力学性质，确定药效研究的最佳给药方案。(3)在人肺泡细胞损伤组织培养模型中，定量检测β-环糊精衍生物对α-溶血素的抑制作用。(4)评价β-环糊精衍生物对金黄色葡萄球菌肺炎的防治作用。这项可行性研究得出的数据将为未来预防和治疗金黄色葡萄球菌肺炎的策略奠定基础，包括由甲氧西林耐药菌株引起的感染。从长远来看，这些化合物的后续临床前和临床研究将导致抗金黄色葡萄球菌感染的新药的开发。公共卫生相关性：金黄色葡萄球菌是严重医院和社区获得性细菌感染的最重要原因之一，近十年来，严重金黄色葡萄球菌肺炎的发病率急剧上升已被注意到。金黄色葡萄球菌菌株之间抗药性的增加，以及社区内这种病原体特别毒力菌株的出现，使得传统的抗菌疗法过时，导致死亡率和护理费用的增加。预防和治疗金黄色葡萄球菌介导的侵袭性肺部感染，特别是耐甲氧西林金黄色葡萄球菌(MRSA)的新的治疗方法是必要的。

DESCRIPTION (provided by applicant): We have recently demonstrated that alpha-hemolysin produced by S. aureus plays a key role in the pathogenesis of staphylococcal pneumonia, and identified beta-cyclodextrin derivatives that potently inhibit the cytotoxic effects of this secreted bacterial toxin. The overall goal of this feasibility study is to examine the ability of these inhibitors to provide in vivo protection in a mouse model of S. aureus pneumonia. The specific aims of this Phase I study are: (1) Establish and validate analytical methods for the detection of cyclodextrins in biological samples. (2) Evaluate toxicity and preliminary pharmacokinetic properties of the compounds and determine the optimal dosing schedules for the efficacy studies. (3) Quantify alpha-hemolysin inhibition by beta-cyclodextrin derivatives in a tissue culture model of human alveolar cell injury. (4) Evaluate the efficacy of beta-cyclodextrin derivatives in the prevention and treatment of S. aureus pneumonia in mice. The data derived from this feasibility study will lay the foundation for future prophylactic and therapeutic strategies in S. aureus pneumonia, including infection caused by methicillin resistant strains. In the long-term, subsequent pre-clinical and clinical studies of these compounds will lead to the development of novel drugs against S. aureus infection. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus is one of the most significant causes of serious hospital- and community-acquired bacterial infections, and a sharp increase in the incidence of severe S. aureus pneumonia has been noted for nearly a decade. Increasing antimicrobial resistance among S. aureus strains and the appearance of particularly virulent isolates of this pathogen within the community have rendered conventional antimicrobial therapies obsolete, resulting in increased mortality and cost of care. Novel therapeutic approaches to both prevent and treat S. aureus-mediated invasive pulmonary infection, especially methicillin resistant S. aureus (MRSA), are necessary.