identification of small molecule inhibitors of clostridium perfringens ε-toxin cytotoxicity using a cell-based high-throughput screen确定小分子抑制剂的梭状芽胞杆菌perfringensε-toxin使用细胞筛选细胞毒性.pdfVIP

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identification of small molecule inhibitors of clostridium perfringens ε-toxin cytotoxicity using a cell-based high-throughput screen确定小分子抑制剂的梭状芽胞杆菌perfringensε-toxin使用细胞筛选细胞毒性.pdf

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identification of small molecule inhibitors of clostridium perfringens ε-toxin cytotoxicity using a cell-based high-throughput screen确定小分子抑制剂的梭状芽胞杆菌perfringensε-toxin使用细胞筛选细胞毒性

Toxins 2010, 2, 1825-1847; doi:10.3390/toxins2071825 OPEN ACCESS toxins ISSN 2072-6651 /journal/toxins Article Identification of Small Molecule Inhibitors of Clostridium perfringens ε-Toxin Cytotoxicity Using a Cell-Based High-Throughput Screen Michelle Lewis 1, Charles David Weaver 1,2 and Mark S. McClain 3,* 1 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235, USA; E-Mail: michelle.lewis@ 2 Department of Pharmacology, Vanderbilt University, Nashville, TN 37235, USA; E-Mail: david.weaver@ 3 Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA * Author to whom correspondence should be addressed; E-Mail: mark.mcclain@; Tel.: +1-615-322-2035; Fax: +1-615-343-6160. Received: 14 May 2010; in revised form: 23 June 2010 / Accepted: 6 July 2010 / Published: 9 July 2010 Abstract: The Clostridium perfringens epsilon toxin, a select agent, is responsible for a severe, often fatal enterotoxemia characterized by edema in the heart, lungs, kidney, and brain. The toxin is believed to be an oligomeric pore-forming toxin. Currently, there is no effective therapy for countering the cytotoxic activity of the toxin in exposed individuals. Using a robust cell-based high-throughput screening (HTS) assay, we screened a 151,616-compound library for the ability to inhibit ε-toxin-induced cytotoxicity. Survival of MDCK cells exposed to the toxin was assessed by addition of resazurin to detect metabolic act