MECHANISM OF ACTION OF NOVEL ANTIFUNGAL COMPOUNDS

最常见的艾滋病相关真菌感染是隐球菌病和念珠菌病。 毒性，缺乏疗效，以及对现有药物的耐药性 抗真菌剂要求需要新的治疗方法。 的总目标 本项目的目的是（a）调查选定的 原型杀真菌天然产物和（B）鉴定和表征 具有设计新疗法潜力的分子靶点，包括 体外分析系统的发展，将是有用的， 发现新的治疗和预防艾滋病相关疾病的方法， 真菌Oi. 为实现这些总体目标， 将被追究; 1. 评价所选先导化合物对一般 在敏感的酵母细胞中的生化过程。 2. 评价所选原型抗真菌化合物的相互作用 与已知抗真菌剂的靶标，即，几丁质合成酶， 葡聚糖合酶，麦角甾醇结合，麦角甾醇生物合成，蛋白质 合成或甘露聚糖结合。 3. 评价所选原型化合物与其他化合物的效果 潜在的抗真菌目标。 也就是说，拓扑异构酶I或II，DNA结合， 多胺合成和细胞渗透性。 4. 对于似乎不通过已知机制起作用的化合物，请确定 并通过使用分子，热力学， 和生物化学特性。 5. 研究“逆转”体外测定系统对 抑制特定真菌靶标的新型抗真菌剂的检测 (i.e.,铁载体的产生，多胺的合成，分泌型铁载体的产生 C.白色念珠菌，多糖荚膜形成与黑色素 在新型隐球菌（Cryptococcus neoformans）中产生）。

The most common AIDS-related fungal Ol are cryptococcosis and candidiasis. The toxicities, lack of efficacy, and development of resistance to existing antifungal agents mandate the need for new therapies. The overall goals of this project are (a) to investigate the mechanism(s) of action of selected prototype fungicidal natural products and (b) to identify and characterize molecular targets with potential for the design of new therapies, including the development of in vitro assay systems that will be useful in the discovery of new therapeutic and prophylactic treatments for AIDS-related fungal Oi. To meet these overall objectives, the following specific aims will be pursued; 1. Evaluate the effects(s) of the selected lead compounds on general biochemical processes i the susceptible yeast cells. 2. Evaluate the interaction of the selected prototype antifungal compounds with the targets of known antifungal agents, i.e., chitin synthetase, glucan synthase, ergosterol binding, ergosterol biosynthesis, protein synthesis, or mannan binding. 3. Evaluate the effect(s) of the selected prototype compounds with other potential antifungal targets. i.e., topoisomerase I or II, DNA binding, polyamine synthesis and cell permeability. 4. For compounds that do not appear to act by a known mechanism, identify and characterize the molecular targets by use of molecular, thermodynamic, and biochemical properties. 5. Investigate the utility of a "reversal" in vitro assay system for the detection of novel antifungal agents that inhibit specific fungal targets (i.e., siderophore production, polyamine synthesis, production of secreted proteinases in C. albicans, polysaccharide capsule formation and melanin production in Cryptococcus neoformans).