In vivo Testing of S. aureus alpha-Hemolysin Inhibitors

描述（由申请人提供）：我们最近证明了由S.金黄色葡萄球菌在葡萄球菌性肺炎的发病机制中起关键作用，并鉴定了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。本可行性研究的总体目标是检查这些抑制剂在S.金黄色肺炎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检测方法。(2)评价化合物的毒性和初步药代动力学特性，并确定疗效研究的最佳给药方案。(3)在人肺泡细胞损伤的组织培养模型中定量β-环糊精衍生物对α-溶血素的抑制。(4)评价β-环糊精衍生物在预防和治疗S.小鼠金黄色葡萄球菌肺炎。本研究的结果将为今后的防治策略奠定基础。金黄色葡萄球菌肺炎，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S.金黄色葡萄球菌感染。公共卫生相关性：金黄色葡萄球菌是严重的医院和社区获得性细菌感染的最重要原因之一，并且严重的金黄色葡萄球菌的发病率急剧增加。金黄色葡萄球菌肺炎已经被注意到近十年。S.金黄色葡萄球菌菌株和社区内该病原体的特别强毒分离株的出现已经使常规抗微生物疗法过时，导致死亡率和护理成本增加。预防和治疗S.金黄色葡萄球菌介导的侵袭性肺部感染，尤其是耐甲氧西林的S.金黄色葡萄球菌（MRSA）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.