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: 3455932
• 负责人: Tadeusz F Molinski
• 金额: $ 11.09万
• 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 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3455932
• 关键词: AIDS; Candida albicans; Cnidaria; Escherichia coli; Porifera; Pseudomonas aeruginosa; Staphylococcus aureus; amphotericin B; antiAIDS agent; antifungal agents; chemical structure; human immunodeficiency virus; 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.

艾滋病毒呈阳性的患者会表现出一系列症状 免疫能力受损的特征，包括易感性 机会性真菌感染。 真菌病如念珠菌病， 在这些病例中，组织胞浆菌病和隐球菌病通常具有侵袭性 并常规接受静脉注射两性霉素 B 治疗。 两性霉素 B 的作用机制涉及选择性膜 然而，多烯的高毒性会破坏酵母细胞 大环内酯类药物在艾滋病患者治疗中存在问题；毒性较低的抗真菌药物 显然需要具有相同的作用机制。 海洋无脊椎动物 海绵、被囊动物和软体动物等是多种新生物的天然来源 天然产品，其中一些具有抗真菌特性。 一些抗生素来自 海洋藏獒（刺胞动物门，藏獒亚纲，藏獒科） 已有报道，但尚未系统地研究过马铃薯 尽管有化合物的指示，但仍研究了抗真菌化合物 具有高生物活性，如海龟毒素。 在此建议， 到 1. 系统调查温带和热带海洋藏花 采用选择性机制的抗真菌有机化合物海绵 我们的实验室开发了测定法。 2. 分离、纯化和化学表征新的抗真菌化合物 潜力导致化疗药物可用于治疗 免疫功能低下患者的机会性系统性真菌病。 3. 比较新型抗真菌药物的活性和作用机制 两性霉素 B 鉴定新的杀菌剂。 4. 确定新化合物的结构，特别是绝对构型 使用光谱技术的抗真菌剂。 5. 评估从机制选择性筛选中确定的化合物： 膜活性，用于体外抗 HIV 活性。 将收集、提取并提取藏羚羊和共存的无脊椎动物 测定抗真菌活性。 活性提取物将使用分离 生物测定引导的分级分离和抗真菌化合物的分离， 纯化并表征。 新型抗真菌药物的结构将 通过光谱技术测定。 新的活性机制 化合物将通过一种新的检测方法进行简要检查，该检测方法比较了模式 与两性霉素 B 的作用来鉴定具有相似作用的化合物 行动方式。 这将有助于识别新的模式 抗真菌活性，并鉴定那些选择性地发挥作用的化合物 与甾醇结合，甾醇是两性霉素 B 活性的基础。 因为后者 还负责两性霉素 B 的新型抗 HIV 活性 甲酯，这项工作可能会发现抑制艾滋病毒的新药物 复制。