Azoles and Candida in AIDS - A Whole Cell Response

描述（由申请人提供）：唑类抗真菌药的使用，包括 氟康唑，用于治疗和/或预防 白色念珠菌导致最近念珠菌菌株急剧增加 对抗真菌药物有抗药性的细菌这是真实的口腔念珠菌病， 艾滋病患者，以及最近被记录的其他免疫受损的 包括血液和骨髓移植受体（BMT）的个体。过去 几年来，唑类耐药的基本分子机制已经被 鉴定包括目标酶的过度表达和两种类型的 外排泵和靶酶突变。来自此的最新数据 实验室和其他人已经表明，抗性是一种全细胞反应， 哪些毒力决定因子可以影响抗性， 决定子可以对这些其他毒力因子产生影响。这整个 细胞应答包括鉴定的异质性抗性（Het-R）表型 在我们的实验室中，某些敏感的分离物能够形成小的 在含有氟康唑的琼脂平板上的菌落。这种Het-R表型可能是 与在这些菌株中诱导真正抗性的能力相关， 与细菌的异质耐药性有关。 这个项目的总体目标是发展对整体的理解 C.白色念珠菌对唑类抗氟林药物，包括Het-R 表型该提案的具体目标是：1）描述 C.抗性与毒力因子间的相互作用白色念珠菌，2）至 表征与整个细胞相关的转录调控 反应，以及3）将该Het-R表型表征为特定的全细胞 反应抗真菌药物耐药性和敏感性测试已成为 由于侵袭性念珠菌病已经成为导致 全球医院感染。本提案中概述的分析将 定义了细胞对唑类抗真菌药物的许多反应中的一些，因此 为我们提供了发展有效的 预防、诊断或治疗真菌感染的策略。

DESCRIPTION (provided by applicant): The use of azole antifungals, including fluconazole, for treatment and/or prophylaxis against infections caused by Candida albicans has resulted in a recent, dramatic increase in Candida strains that are resistant to antifungal drugs. This is true in oral candidiasis in AIDS patients, and has recently been documented in other immune compromised individuals including blood and marrow transplant recipients (BMT). In the past several years, the basic molecular mechanisms of azole resistance have been identified including the overexpression of the target enzyme and two types of efflux pump, and mutation in the target enzyme. Recent data from this laboratory and others has indicated that resistance is a whole cell response in which virulence determinants can have an effect on resistance, and resistance determinants can have an effect on these other virulence factors. This whole cell response includes a heterogeneous resistance (Het-R) phenotype identified in our laboratory, in which certain susceptible isolates are able to form small colonies on agar plates containing fluconazole. This Het-R phenotype may be correlated with the ability to induce true resistance in these strains, and is related to heterogeneous resistance in bacteria. The overall goal of this project is to develop an understanding of the whole cell response of C. albicans to azole antiflingals, including the Het-R phenotype. The specific aims of this proposal are: 1) to characterize the interactions between resistance and virulence factors of C. albicans, 2) to characterize the transcriptional regulation associated with the whole cell response, and 3) to characterize this Het-R phenotype as a specific whole cell response. Antifungal drug resistance and susceptibility testing has become increasingly important as invasive candidiasis has become a leading cause of nosocomial infections worldwide. The analyses outlined in this proposal will define some of the many responses of a cell to azole antifungal drugs, thus providing us with information critical to the development of effective strategies to prevent, diagnose or treat fungal infections.