AIDS: Combatting drug resistance of Candida albicans

描述（由申请人提供）：白色念珠菌是一种致病性酵母菌，在免疫功能低下和对抗性患者中引起严重的真菌感染，念珠菌感染可能是HIV+个体免疫抑制的第一个指征。艾滋病患者经常患有口咽念珠菌病，需要抗真菌治疗。在20世纪90年代，由于白色念珠菌菌株对氟康唑产生耐药性，氟康唑治疗艾滋病OPC患者失败的情况急剧增加。在这些酵母菌中，导致高水平氟康唑耐药性的最常见机制是药物外排泵Cdrl p的过度表达。在全球范围内，OFC仍然是hiv - aids的主要对抗性感染，氟康唑在第三世界的广泛使用可能会对白色念珠菌产生耐药性保持压力。本研究的总体目标是使用一种新的策略，通过对抗白色念珠菌的氮耐药性来改善艾滋病患者口腔念珠菌病的治疗。具体目标是：

DESCRIPTION (provided by applicant): Candida albicans is a pathogenic yeast that causes serious fungal infections in the immunocompromised and opponunistic Candida infections can be the first indication of immunosuppression in HIV+ individuals. AIDS patients frequently suffer from oropharyngeal candidiasis (OPC) and require antifungal therapy. In the 1990s there was a dramatic increase in the failure of fluconazole therapy for AIDS patients with OPC due to C. albicans strains developing fluconazole resistance. The most common mechanism responsible for high level fluconazole resistance in these yeast was over-expression of drug efflux pump Cdrl p. Globally, OFC remains a major opponunistic infection in HIVIAIDS, and the widespread use of fluconazole in the third world is likely to maintain pressure on C. albicans to develop resistance. The overall objective of this research is to use a novel strategy to improve the treatment of AIDS patients with oral candidiasis by combating azoleresistance in C. albicans. Specific objectives are to: 1. Employ a novel heterologous functional hyper-expression system to determine the mechanism of pumping by Cdrl p, using both in vitro mutagenized Cdrl p and Cdrl proteins from clinical C. albicans isolates (obtained from AIDS patients) that demonstrate high and low pump activities. 2. Use the heterologous functional hyper-expression of Cdrlp to screen a unique combinatorial Doctapeptide library for peptides that inhibit the pump. This work will validate a novel approach to combating azole-resistance in C. albicana An understanding of drug pumping mechanisms may indicate new ways to circumvent efflux-mediated resistance. This project is expected to identify a lead compound with the potential to sensitize resistant strains to azole antifungals.