Novel Azole Resistance Mechanisms in Candida albicans

白色念珠菌的新唑耐药机制

基本信息

批准号：
7847583
负责人：
P. David Rogers
金额：
$ 37万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2011-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847583
关键词：
ABCB1 gene Acquired Immunodeficiency Syndrome Alleles Amino Acid Substitution Antifungal Agents Azole resistance Azoles Candida albicans Chromosomes Clinical Country Cutaneous Fluconazole Fluconazole resistance Frequencies Fungal Drug Resistance Gene Expression Gene Targeting Genes Goals Highly Active Antiretroviral Therapy Homologous Gene Human Infection Loss of Heterozygosity Mediating Molecular Mutation Opportunistic Infections Patients Pharmaceutical Preparations Pharmacotherapy Predisposition Proteins Regulation Resistance Resistance development Role Saccharomyces cerevisiae Signal Transduction Sterols Systemic infection TAC1 gene Toxic effect Transcription factor genes Treatment Failure United States Up-Regulation Zinc Cluster base cis acting element efflux pump gain of function gain of function mutation improved novel novel strategies oropharyngeal thrush overexpression pathogen patient population resistance mechanism resistant strain trait transcription factor treatment strategy uptake

项目摘要

C. albicans is an opportunistic human fungal pathogen that causes mucosal, cutaneous, and systemic infections including oropharyngeal candidiasis (OPC), the most frequent opportunistic infection among patients suffering from AIDS. Fluconazole and other azole antifungal agents have proven effective in the management of OPC; however, with increased use of these agents, treatment failures have occurred that have been associated with the emergence of azole-resistant strains of C. albicans. While the use of highly active antiretroviral therapy (HAART) has reduced the frequency of OPC among AIDS patients in the United States, limited access to such therapy in underdeveloped countries, poor compliance, and toxicity associated with HAART will likely contribute to an increase in this problem among AIDS patients world-wide. While several mechanisms of azole resistance have been described, these are not sufficient to explain this trait in many clinical isolates. We have discovered MRR1 which encodes the transcriptional regulator of the MDR1 efflux pump gene and is a central regulator or azole antifungal resistance in C. albicans. Gain-of-function mutations in the MRR1 gene result in the constitutive activation of this transcription factor, up-regulation of MDR1, and increased fluconazole resistance. The specific aims outlined in the current proposal represent the next steps towards achieving our overall goal of understanding how Mrr1p influences azole resistance in C. albicans. We will identify direct and indirect target genes of Mrr1p, elucidate their cis-acting elements, and determine which of these genes influence Mrr1p-mediated azole resistance. We will also identify accessory proteins that associate with Mrr1p and determine if these accessory proteins influence Mrr1p-mediated azole resistance. These studies will further elucidate the molecular basis for azole antifungal resistance and will ultimately point to novel strategies for predicting treatment failure, overcoming azole resistance, and improving antifungal pharmacotherapy in this patient population.

白色念珠菌是一种机会性人类真菌病原体，可引起粘膜、皮肤和全身感染，包括口咽念珠菌病 (OPC)，这是艾滋病患者中最常见的机会性感染。氟康唑和其他唑类抗真菌药物已被证明可有效治疗 OPC；然而，随着这些药物的使用增加，出现了与唑类抗性白色念珠菌菌株的出现相关的治疗失败。虽然高效抗逆转录病毒疗法 (HAART) 的使用降低了美国 AIDS 患者中 OPC 的发生率，但在不发达国家，获得此类疗法的机会有限、依从性差以及与 HAART 相关的毒性可能会导致这种情况的增加。全世界艾滋病患者面临的问题。虽然已经描述了几种唑类耐药机制，但这些机制不足以解释许多临床分离株的这一特征。我们发现 MRR1 编码 MDR1 外排泵基因的转录调节因子，并且是白色念珠菌中唑类抗真菌耐药性的中心调节因子。 MRR1 基因的功能获得性突变导致该转录因子的组成型激活、MDR1 上调以及氟康唑耐药性增加。当前提案中概述的具体目标代表了实现我们了解 Mrr1p 如何影响白色念珠菌唑耐药性的总体目标的下一步。我们将鉴定 Mrr1p 的直接和间接靶基因，阐明其顺式作用元件，并确定这些基因中哪些影响 Mrr1p 介导的唑类耐药性。我们还将鉴定与 Mrr1p 相关的辅助蛋白，并确定这些辅助蛋白是否影响 Mrr1p 介导的唑类耐药性。这些研究将进一步阐明唑类抗真菌耐药性的分子基础，并最终指出预测治疗失败、克服唑类耐药性和改善该患者群体抗真菌药物治疗的新策略。