Azoles and Candida in AIDS - A Whole Cell Response

艾滋病中的唑类和​​念珠菌 - 全细胞反应

• 批准号: 6711085
• 负责人: Theodore C. White
• 金额: $ 36.61万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711085
• 关键词: AIDS therapy; Candida albicans; antifungal agents; azoles; candidiasis; clinical research; drug resistance; drug screening /evaluation; fungal genetics; gene expression; genetic regulation; genetic strain; genetic transcription; human subject; human therapy evaluation; microarray technology; microorganism disease chemotherapy; opportunistic infections; pharmacokinetics; phenotype; virulence

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.

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/或预防由以下原因引起的感染 白色念珠菌导致念珠菌菌株最近急剧增加 对抗真菌药物有抗药性。口腔念珠菌病也是如此 艾滋病患者，最近在其他免疫受损的患者中也有记录 个人，包括血液和骨髓移植受者 (BMT)。在过去 多年来，唑类耐药的基本分子机制已被阐明 鉴定包括目标酶的过度表达和两种类型 外排泵和目标酶的突变。最新数据来自于此 实验室和其他人已经表明，耐药性是一种全细胞反应 哪些毒力决定因素可以对耐药性产生影响，以及耐药性 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抗性 (Het-R) 表型 在我们的实验室中，某些易感菌株能够形成小的 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性的能力相关，并且是 与细菌的异质性耐药性有关。 该项目的总体目标是加深对整体的理解 白色念珠菌对唑类抗真菌药（包括 Het-R）的细胞反应 表型。该提案的具体目标是：1）描述 白色念珠菌的耐药性和毒力因子之间的相互作用，2) 表征与全细胞相关的转录调控 响应，以及 3) 将 Het-R 表型表征为特定的全细胞 回复。抗真菌药物耐药性和药敏检测已成为 随着侵袭性念珠菌病已成为导致感染的主要原因，这一点变得越来越重要 全世界的医院感染。本提案中概述的分析将 定义了细胞对唑类抗真菌药物的多种反应中的一些反应，因此 为我们提供对开发有效的信息至关重要的信息 预防、诊断或治疗真菌感染的策略。