New Drugs for Opportunistic Infections

描述(申请人提供)：该项目的总体目标是确定新的化合物，以及发现新化合物的新途径，以开发治疗与艾滋病和癌症相关的主要播散性真菌感染的新方法。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验证的新型抗真菌化合物。我们的方法是验证前一个项目期间确定的具有抗真菌和逆转耐药性的独特先导化合物，确定它们的作用机制，并评估它们对耐药菌株的体内效果。该项目的具体目标是：1.通过外排泵分析和基因组方法验证显示逆转氟康唑耐药性的新的先导化合物(已有)；2.使用基因组图谱方法确定铅抗真菌化合物的作用机制，并验证使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系统性真菌病小鼠模型中的体内疗效，包括对耐药菌株的活性；以及4.确定其他具有独特机制特征的新先导化合物。 拟议工作的成功完成将产生新的先导化合物原型，这些化合物将作为开发新类别抗真菌药的模板，作为开发与现有抗真菌药结合使用的新药的模板，并作为确定新作用机制的探针，可在未来寻找其他新的衍生物。这些信息将扩大关于这些感染的治疗控制的知识基础，并了解这些病原体的基本生物学。

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.