NEW DRUGS FOR OPPORTUNISTIC INFECTIOUS DISEASES

治疗机会性传染病的新药

• 批准号: 2376326
• 负责人: ALICE M. CLARK
• 金额: $ 18.46万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2376326
• 关键词: AIDS; Candida albicans; Cryptococcus neoformans; Mycobacterium intracellulare; antibacterial agents; antifungal agents; chemical structure function; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; laboratory mouse; microorganism disease chemotherapy; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; opportunistic infections; plant extracts; tissue /cell culture

The objective of this project is to discover new prototype antibiotics with potential utility specifically for the treatment of AIDS-related opportunistic disseminated mycoses and mycobacteriosis. Acquired immunodeficiency Syndrome (AIDS) is characterized by a breakdown in the immune system which is manifested in the form of serious opportunistic infections. Treatment of such infections is often inadequate for a variety of reasons, including lack of effective antimicrobial therapy. Historically, most bacterial infections and localized fungal infections have been effectively treated with one of the numerous clinically available antibiotics. However, the need for new, more effective and less toxic antibiotics for the treatment of disseminated fungal and mycobacterial infections is obvious in light of the significant toxicities and failure rates of the currently available agents. The discovery of new antibiotics has in the past successfully relied primarily upon the isolation of such agents from natural sources. The major advantage of this approach over chemical synthesis or modification of existing agents is the likelihood of identifying new prototype drugs with quite different chemical structures, and hence, less likelihood of similar toxicities, cross-resistance, and mechanisms of action. Although microorganisms have traditionally served as the primary source of new antibiotics, it has recently been shown that higher plants also serve as sources for a number of diverse and novel antimicrobial agents. The goal of the project, to identify prototype antibiotics for AIDS related 01, will be accomplished by the initial in vitro evaluation of antifungal and antimycobacterial activity of extracts of higher plants. Plant extracts which show good activity will be fractionated and purified using a bioassay-directed scheme. This approach ensures that relatively little time and effort will be wasted in isolating inactive materials. Pure active compounds with significant minimum inhibitory concentrations (MIC) and relatively low in vitro cytotoxicity to mammalian cells will be evaluated for in vivo efficacy in established animal models of disseminated mycosis and mycobacteriosis in order to determine their potential clinical utility.

该项目的目标是发现新的原型抗生素， 特别是治疗艾滋病相关的潜在效用 机会性播散性真菌病和分枝杆菌病。 获得性免疫缺陷综合症（艾滋病）的特点是 在免疫系统中表现为严重的 机会性感染 对这类感染的治疗往往不足 由于各种原因，包括缺乏有效的抗菌剂， 疗法 历史上，大多数细菌感染和局部真菌感染 已经有效地治疗了众多的临床可用的 抗生素 然而，需要新的，更有效和毒性更小的 用于治疗播散性真菌和分枝杆菌的抗生素 感染是显而易见的鉴于显着的毒性和失败 当前可用代理商的费率。 新抗生素的发现 在过去，成功地主要依赖于这种隔离 天然来源的代理商。 这种方法的主要优点是， 现有药剂的化学合成或修饰是可能的， 识别出化学结构完全不同的新原型药物， 因此，类似毒性、交叉耐药性和 作用机制。 虽然微生物在传统上是 作为新抗生素的主要来源，最近的研究表明， 高等植物也是多种多样和新颖的植物的来源。 抗菌剂。 该项目的目标是确定与艾滋病有关的原型抗生素 01，将完成初步的体外评价抗真菌 和高等植物提取物的抗分枝杆菌活性。 植物 显示出良好活性的提取物将被分级分离并纯化， 一个生物测定导向的方案。 这种方法确保了相对较少的 在分离非活性材料时将浪费时间和精力。 纯 具有显著最小抑菌浓度（MIC）的活性化合物 并且对哺乳动物细胞的体外细胞毒性相对较低， 评价了在已建立的播散性骨髓瘤动物模型中的体内功效。 真菌病和分枝杆菌病，以确定其潜在的临床 效用