Mechanism-of-Action Determination of GMP Synthase Inhibitors and Target Validation in Candida albicans and Aspergillus fumigatus
- 作者：Roberto Rodriguez-Suarez ; Deming Xu ; Karynn Veillette ; John Davison ; Susan Sillaots ; Sarah Kauffman ; Wenqi Hu ; Joel Bowman ; Nick Martel ; Steve Trosok ; Hao Wang ; Li Zhang ; Li-Yin Huang ; Yang Li ; Fariba
- 关键词：CHEMBIO ; SIGNALING
- 刊名：Chemistry & Biology
- 出版年：2007
- 期刊代码：20_10745521
- 类别：ch
- 出版时间：26 October 2007
- 卷：14
- 期：10
- 页码：1163-1175
- 文件大小：1475 K
摘要
Mechanism-of-action (MOA) studies of bioactive compounds are fundamental to drug discovery. However, in vitro studies alone may not recapitulate a compound's MOA in whole cells. Here, we apply a chemogenomics approach in Candida albicans to evaluate compounds affecting purine metabolism. They include the IMP dehydrogenase inhibitors mycophenolic acid and mizoribine and the previously reported GMP synthase inhibitors acivicin and 6-diazo-5-oxo-L-norleucine (DON). We report important aspects of their whole-cell activity, including their primary target, off-target activity, and drug metabolism. Further, we describe ECC1385, an inhibitor of GMP synthase, and provide biochemical and genetic evidence supporting its MOA to be distinct from acivicin or DON. Importantly, GMP synthase activity is conditionally essential in C. albicans and Aspergillus fumigatus and is required for virulence of both pathogens, thus constituting an unexpected antifungal target.