Dissecting triazole resistance and transcriptional regulation of ergosterol homeo

描述（由申请方提供）：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。三唑类抗真菌药物是临床应用最多的一类抗真菌药物。它们抑制羊毛甾醇14-脱甲基酶（Erg 11）。三唑类药物的治疗效果因耐药菌株的出现而受到损害。C.白色念珠菌可以通过多种不同的机制获得三唑抗性，包括科普药物诱导的细胞应激的机制。upc 2是麦角甾醇生物合成途径基因的转录调控因子，对三唑类药物的耐药性起着关键作用。我们发现，Cph 2也是麦角固醇生物合成的调节剂，Cph 2的失调导致药物敏感性改变。Upc 2和Cph 2在C.白色不清楚。在这里，我们建议使用化学方法来剖析Cph 2和UPc 2的调控机制。目的1鉴定麦角固醇稳态转录调控靶向小分子。目的2鉴定C.白色念珠菌的化学基因组学方法。目标3将是目标验证和功能特性的C。白色念珠菌小分子及其靶点的鉴定将有助于发现控制麦角固醇稳态和三唑类药物耐药的新途径和机制。

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.