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首页> 外文期刊>Chemistry & biology >Mechanism-of-action determination of GMP synthase inhibitors and target validation in Candida albicans and Aspergillus fumigatus
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Mechanism-of-action determination of GMP synthase inhibitors and target validation in Candida albicans and Aspergillus fumigatus

机译：念珠菌和烟曲霉中GMP合酶抑制剂的作用机理测定和靶标验证

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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.
机译：生物活性化合物的作用机理（MOA）研究是药物发现的基础。但是，仅在体外研究可能无法在全细胞中概括化合物的MOA。在这里，我们在白色念珠菌中应用化学基因组学方法来评估影响嘌呤代谢的化合物。它们包括IMP脱氢酶抑制剂麦考酚酸和咪唑啉碱，以及先前报道的GMP合酶抑制剂阿西维汀和6-重氮基5-氧代-L-正亮氨酸（DON）。我们报告了其全细胞活性的重要方面，包括其主要靶标，脱靶活性和药物代谢。此外，我们描述了ECC1385，一种GMP合酶的抑制剂，并提供了支持其MOA与阿西维奇或DON不同的生化和遗传证据。重要的是，GMP合酶活性在白色念珠菌和烟曲霉中是条件性必需的，并且对于两种病原体的毒力都是必需的，因此构成了意想不到的抗真菌靶标。

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