MECHANISM-SELECTIVE ANTIFUNGALS--POTENTIAL AIDS ADJUVANT

机制选择性抗真菌药--潜在的艾滋病佐剂

• 批准号: 2066647
• 负责人: Tadeusz F Molinski
• 金额: $ 10.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2066647
• 关键词: AIDS; Candida albicans; Cnidaria; Escherichia coli; Porifera; Pseudomonas aeruginosa; Staphylococcus aureus; alternatives to animals in research; amphotericin B; antiAIDS agent; antifungal agents; biological products; chemical structure; human immunodeficiency virus; immunomodulators; microorganism culture; mycosis; opportunistic infections

HIV positive patients suffering AIDS manifest a host of symptoms characteristic of impaired immuno-competency including susceptibility to opportunistic fungal infections. Mycoses such as candidiasis, histoplasmosis and cryptococcosis are frequently invasive in these cases and have been routinely treated with intravenous amphotericin B. The mechanism of action of amphotericin B involves selective membrane disruption of yeast cells, however, the high toxicity of the polyene macrolides is problematic in AIDS patient treatment; less toxic antifungals with the same mechanism of action are clearly needed. Marine invertebrates such as sponges, tunicates and molluscs are natural sources of diverse new natural products, some with antifungal properties. A few antibiotics from marine zoanthids (phylum Cnidaria, Subclass Zoantharia, order Zoanthidae) have been reported, however, zoanthids have not been systematically investigated for antifungal compounds, despite the indication of compounds with high biological activity such as palytoxin. It is proposed, herein, to 1. Systematically survey temperate and tropical marine zoanthids and sponges for antifungal organic compounds employing a mechanisms selective assay developed in our laboratories. 2. Isolate, purify and chemically characterize new antifungal compounds as potential leads to chemotherapeutics with utility in treatment of opportunistic systemic mycoses in immunocompromised patients. 3. Compare the activity and mechanisms of action of new antifungals with amphotericin B to identify new fungicidal agents. 4. Determine the structures, especially absolute configuration, of new antifungal agents using spectroscopic techniques. 5. Evaluate compounds, identified from the mechanism-selective screen as membrane active, for in vitro anti-HIV activity. Zoanthids and co-occurring invertebrates will be collected, extracted and assayed for antifungal activity. Active extracts will be separated using a bioassay guided fractionation and the antifungal compounds isolated, purified and characterized. Structures of new antifungals will be determined by spectroscopic techniques. The mechanisms of activity of new compounds will be briefly examined by a novel assay which compares the mode of action with that of amphotericin B to identify compounds with similar modes of action. This will aid in the identification of new modes of antifungal activity and also identify those compounds which selectively bind to sterol, the basis of amphotericin B activity. Because the latter is also responsible for the novel anti-HIV activity of amphotericin B methyl ester, this work may uncover new agents which inhibit HIV replication.

艾滋病毒阳性患者遭受艾滋病表现出许多症状 免疫能力受损的特征，包括对 机会性真菌感染。 mycoses，例如念珠菌病， 在这些情况下 并经常用静脉注射蛋白B处理。 两性霉素B的作用机理涉及选择性膜 然而，酵母细胞的破坏是多烯的高毒性 大环内酯类在艾滋病患者治疗中是有问题的。毒性较小的抗真菌性 显然需要具有相同的作用机理。 海洋无脊椎动物 例如海绵，双膜和软体动物是多种新的自然来源 天然产物，有些具有抗真菌特性。 一些抗生素 海洋Zoanthids（门cnidaria，子类Zoantharia，订购Zoanthidae） 但是，已经报道了zoanthids尚未系统地 尽管有化合物的指示，但仍研究了抗真菌化合物 具有较高的生物学活性，例如呼毒素。 在此提出了 到 1。系统地调查温带和热带海洋Zoanthids和 使用一种机制选择性的抗真菌有机化合物的海绵 在我们的实验室中开发的测定。 2。分离，纯化和化学表征新的抗真菌化合物 潜在导致化学治疗药，并在治疗 免疫功能低下的患者的机会性全身性真菌性。 3。比较新抗真菌剂的活性和机制 两性霉素B鉴定新的杀真菌剂。 4。确定新的结构，尤其是绝对配置 使用光谱技术的抗真菌剂。 5。评估化合物，从机理选择性屏幕上标识为 膜活性，用于体外抗HIV活性。 将收集，提取Zoanthids和同时存在的无脊椎动物，并 分析用于抗真菌活性。 主动提取物将使用 生物测定的引导分级和分离的抗真菌化合物， 纯化和特征。 新抗真菌的结构将是 由光谱技术确定。 新活动的机制 将通过一种比较模式的新颖测定法对化合物进行简要检查 带有两性霉素B的作用，以识别具有相似的化合物 动作模式。 这将有助于确定新模式 抗真菌活性，还识别那些有选择性的化合物 与固醇（两性霉素B活性的基础）结合。 因为后者 还负责两性霉素B的新型抗HIV活性 甲基酯，这项工作可能会发现抑制HIV的新药物 复制。