Azoles and Candida in AIDS - A Whole Cell Response

说明(申请人提供)：唑类抗真菌药物的使用情况，包括 氟康唑，用于治疗和/或预防由 白色念珠菌导致最近白色念珠菌菌株的急剧增加 对抗真菌药物有抗药性的人。这在#年口腔念珠菌病中是正确的。 艾滋病患者，以及最近被记录的其他免疫功能受损 包括血液和骨髓移植受者(BMT)在内的个人。在过去 几年来，唑类耐药的基本分子机制是 鉴定包括目标酶的过表达和两种类型的 外排泵和靶酶的突变。最近的数据来自这个 实验室和其他人已经表明，抗性是一种完整的细胞反应 哪些毒力决定因素会对抗药性产生影响 决定因素可以对这些其他毒力因素产生影响。这整个 细胞反应包括已鉴定的异质性耐药(Het-R)表型 在我们的实验室里，某些敏感的菌株能够形成小的 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药性的能力相关，并且是 与细菌中的异质性耐药有关。 这个项目的总体目标是发展对整体的理解 白念珠菌对包括Het-R在内的唑类抗菌药物的细胞反应 表型。这项建议的具体目标是：1)描述 白念珠菌耐药性与毒力因子的相互作用 描述与整个细胞相关的转录调控 反应，以及3)将这种Het-R表型表征为特定的整个细胞 回应。抗真菌耐药性和药敏检测已经成为 随着侵袭性念珠菌病成为 世界各地的医院感染。本提案中概述的分析将 定义细胞对唑类抗真菌药物的许多反应中的一些，如 为我们提供对发展有效的 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.