In vivo Testing of S. aureus alpha-Hemolysin Inhibitors

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.