Dissecting triazole resistance and transcriptional regulation of ergosterol homeo

描述（由申请人提供）：白色念珠菌是人类的主要真菌病原体，在免疫功能低下的个体中引起危及生命的感染。念珠菌病的治疗受到抗真菌药物数量有限的阻碍。三唑类药物是临床使用的最大一类抗真菌药物。它们抑制羊毛甾醇14-去甲基化酶（Erg11）。耐药菌株的出现削弱了三唑类药物的治疗效果。白色念珠菌可以通过多种不同的机制获得三唑耐药性，包括应对药物诱导的细胞应激的机制。Upc2是麦角甾醇生物合成途径基因的转录调节因子，对三唑类药物的抗性至关重要。我们发现Cph2也是麦角甾醇生物合成的调节因子，Cph2的错误调节会导致药物敏感性的改变。Upc2和Cph2在白色念珠菌中的调控机制尚不清楚。在这里，我们建议使用化学方法来剖析Cph2和Upc2的调控机制。目的1确定靶向麦角甾醇稳态转录调控的小分子。目的2通过化学基因组学方法鉴定白色念珠菌中选定的击中化合物的蛋白靶点。目的3将是靶验证和功能表征白色念珠菌。小分子及其靶点的鉴定将导致发现控制麦角甾醇稳态和三唑耐药性的新途径和机制。

DESCRIPTION (provided by applicant): Candida albicans is the leading fungal pathogen of humans, causing life-threatening infection in immunocompromised individuals. Treatment of candidiasis is hampered by the limited number of antifungal drugs. The triazoles are the largest class of antifungal drugs in clinical use. They inhibit lanosterol 14-demethylase (Erg11). The therapeutic efficacy of triazoles is compromised by the emergence of drug resistant strains. C. albicans can acquire triazole resistance by multiple distinct mechanisms, including mechanisms to cope with drug-induced cellular stresses. Upc2, a transcriptional regulator of ergosterol biosynthesis pathway genes, is critical for resistance to triazoles. We find that Cph2 is also a regulator of ergosterol biosynthesis and misregulation of Cph2 leads to altered drug sensitivity. How Upc2 and Cph2 are regulated in C. albicans is unclear. Here we propose to use chemical approaches to dissect regulatory mechanisms for Cph2 and Upc2. Aim 1 identifies small molecules that target transcriptional regulation of ergosterol homeostasis. Aim 2 identifies protein targets of selected hit compounds in C. albicans by chemical genomics approaches. Aim 3 will be target verification and functional characterization in C. albicans. Identification of smal molecules and their targets will lead to the discovery of novel pathways and mechanisms that control ergosterol homeostasis and triazole resistance.