Dissecting triazole resistance and transcriptional regulation of ergosterol homeo

描述(申请人提供)：白色念珠菌是人类的主要真菌病原体，在免疫功能受损的人中会导致危及生命的感染。抗真菌药物的数量有限阻碍了念珠菌病的治疗。三氮唑类药物是临床使用的最大类抗真菌药物。它们抑制羊毛甾醇14-脱甲基酶(Erg11)。三氮唑类药物的治疗效果因出现耐药菌株而受到影响。白念珠菌可通过多种不同的机制获得对三氮唑的耐药性，包括应对药物诱导的细胞压力的机制。UPc2是麦角甾醇生物合成途径基因的转录调控因子，对三氮唑类药物的耐药性起关键作用。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。目前尚不清楚白念珠菌中Upc2和Cph2是如何调控的。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确定以麦角固醇稳态转录调控为靶点的小分子。目的2通过化学基因组学方法确定白念珠菌中选定的命中化合物的蛋白质靶点。目标3将是白念珠菌的靶标验证和功能鉴定。识别SMAL分子及其靶点将有助于发现控制麦角固醇稳态和三氮唑耐药的新途径和新机制。

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.