Novel Azole Resistance Mechanisms in Candida albicans

白色念珠菌的新唑耐药机制

• 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
• 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

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主义的人类真菌病原体，可引起包括口咽念珠菌病（OPC）在内的粘膜，皮肤和全身感染，这是患有艾滋病患者中最常见的机会感染。事实证明，氟康唑和其他唑唑抗真菌剂有效地管理OPC。但是，随着这些药物的使用增加，已经发生了与白色念珠菌抗硫唑菌株的出现有关的治疗失败。虽然使用高度活跃的抗逆转录病毒疗法（HAART）降低了美国艾滋病患者中OPC的频率，在欠发达国家接受这种治疗的机会有限，依从性差和与HAART相关的毒性可能会导致全球艾滋病患者的这一问题的增加。虽然已经描述了硫唑耐药性的几种机制，但这些机制不足以解释许多临床分离株中的这种特征。我们发现了MRR1编码MDR1外排泵基因的转录调节剂，并且是白色念珠菌中的中央调节剂或Azole抗真菌抗性。 MRR1基因的功能性突变导致该转录因子的组成型激活，MDR1的上调和氟康唑抗性增加。当前提案中概述的具体目的代表了实现我们了解MRR1P如何影响白色念珠菌中硫唑的总体目标的下一步。我们将确定MRR1P的直接和间接靶基因，阐明其顺式作用元件，并确定哪些基因影响MRR1P介导的唑抗性。我们还将确定与MRR1P关联的辅助蛋白，并确定这些辅助蛋白是否影响MRR1P介导的偶氮抗性。这些研究将进一步阐明甲唑抗真菌抗性的分子基础，并最终指出预测治疗失败，克服硫唑耐药性并改善该患者人群中抗真菌药物治疗的新型策略。