New Drugs for Opportunistic Infections

描述（由申请人提供）：该项目的总体目标是确定新化合物，以及发现新化合物的新途径，用于开发与艾滋病和癌症相关的主要弥散性真菌感染的新治疗方法。这是R01 AI27094的竞争性更新，扩展了我们目前在抗真菌药物发现领域的工作，重点是鉴定具有机械特征和经过验证的新型抗真菌化合物。我们的方法是验证在上一个项目期间发现的具有抗真菌和逆转耐药性的独特先导化合物，确定其作用机制，并评估其对耐药菌株的体内疗效。本项目的具体目标是：1。通过使用外排泵测定和基因组方法验证显示逆转氟康唑耐药性的新先导化合物（已经在手）；2. 利用基因组分析方法确定主要抗真菌化合物的作用机制，并验证利用遗传和生化策略确定的分子靶点；3. 评估选定的先导化合物在小鼠全身性真菌病模型中的体内功效，包括对耐药菌株的活性；和4。确定其他具有独特机制的新先导化合物。

DESCRIPTION (provided by applicant): The overall goal of this project is to identify new compounds, as well as new pathways to discover new compounds for development of new treatments for the major AIDS- and cancer-related disseminated fungal infections. This is a competitive renewal of R01 AI27094 and expands our current work in the area of antifungal drug discovery, with an emphasis on the identification of mechanistically characterized and validated novel antifungal compounds. Our approach is to validate the unique lead compounds with antifungal and resistance-reversing properties that were identified in the previous project period, determine their mechanisms of action, and evaluate their in vivo efficacies against resistant strains. The specific aims of this project are: 1. Validate new lead compounds (already in hand) that show reversal of fluconazole resistance by using efflux pump assays and genomic approaches; 2. Determine mechanisms of action of lead antifungal compounds using genomic profiling approaches, and validate the molecular targets identified using genetic and biochemical strategies; 3. Evaluate the in vivo efficacy of selected lead compounds in murine models of systemic mycoses, including activity against resistant strains; and, 4. Identify other new lead compounds that exhibit unique mechanistic profiles. Successful completion of the proposed work will yield new prototype lead compounds that will serve as templates for development of new classes of antifungal agents, as templates for the development of new drugs to be used in combination with existing antifungal agents to reverse resistance to these agents, and as probes to identify novel mechanisms of action that can be exploited in the future search for other new derivatives. This information will expand the foundation of knowledge regarding the therapeutic control of these infections and the understanding of the basic biology of these pathogens.