Regulation of Drug Resistance Genes in C. Albicans

描述（由申请人提供）： 本研究旨在探讨白念珠菌耐药基因的调控。超过90%的艾滋病患者患有口咽念珠菌病（OPC）。氟康唑是最常用的抗真菌药物，由于其疗效和缺乏副作用，这些感染。氟康唑治疗失败率上升，最明显的是在接受延长氟康唑治疗的复发性OPC的艾滋病患者中。大多数治疗失败是由于氟康唑耐药的C。白色念珠菌分离株。虽然C.由于多药耐药泵的转录增加，白念珠菌菌株最常表现出增加的药物外排，关于导致这种转录增加的分子机制知之甚少。C.已分离出白念珠菌耐药性突变体，其增加多药外排泵MDR 1和CDR 2的转录。这些突变分为两类：（i）导致MDR1或CDR2高水平表达的反式作用突变，以及（ii）导致MDR1或CDR2转录中更温和的氟康唑依赖性增加的顺式作用启动子突变。拟议的研究将在分子水平上分析这些突变，确定导致这些耐药泵转录增加的机制，并研究药物选择方案对获得这些突变的影响。这些研究的长期目标是在预防、药物剂量方案和氟康唑耐药菌株的发展方面促进更明智地使用氟康唑。

DESCRIPTION (provided by applicant): This research project investigates the regulation of drug resistance genes in Candida albicans. Greater than 90% of AIDS patients suffer from oropharyngeal candidiasis (OPC). Fluconazole is the most commonly prescribed antifungal drug for these infections due to its efficacy and lack of side effects. Treatment failures with fluconazole have risen, most notably in AIDS patients with recurrent OPC that receive extended fluconazole therapy. The majority of treatment failures are due to fluconazole resistant C. albicans isolates. Although resistant C. albicans strain most often exhibit increased drug efflux due to the increased transcription of multidrug resistance pumps, little is known concerning the molecular mechanisms that lead to this increased transcription. C. aibicans drug resistant mutants have been isolated that increase transcription of the multidrug efflux pumps MDR1 and CDR2. These mutations fall into two classes: (i) transacting mutations that lead to high level expression of either MDR1 or CDR2, and (ii) cis-acting promoter mutations that lead to a more moderate, fluconazole-dependent increase in the transcription of either MDR1 or CDR2. The proposed research will analyze these mutations at the molecular level, determine the mechanisms that lead to increased transcription of these drug resistance pumps, and study the influence of drug selection regimens on the acquisition of these mutations. The long-term goal of these studies is to contribute to a more informed use of fluconazole with respect to prophylaxis, drug dosage regimens and the development of fluconazole resistant strains.