Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

作者：Yoon‐Dong Park, Wei Sun, Antonio Salas, Avan Antia, Cindy Carvajal, Amy Wang, Xin Xu, Zhaojin Meng, Ming Zhou, Gregory J. Tawa, Jean Dehdashti, Wei Zheng, Christina Henderson, Adrian M. Zelazny, Peter R. Williamson · 发表于：mBio · 年份：2016 · DOI：10.1128/mbio.01073-16 · 被引用次数：22 · 研究领域：Fungal Infections and Studies、Nail Diseases and Treatments、Antifungal resistance and susceptibility

UNLABELLED: Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. IMPORTANCE: Cryptococcosis is a neglected fungal meningitis that causes approximately half a million deaths annually. The most effective antifungal agent, amphotericin B, was developed in the 1950s, and no effective medicine has been developed for this disease since that time. A key aspect of amphotericin B's effectiveness is thought to be because of its ability to kill the fungus (fungicidal activity), rather than just stop or slow its g...