NEW DRUGS FOR OPPORTUNISTIC INFECTIOUS DISEASES

该项目的目标是发现新的原型抗生素和 专门用于艾滋病相关治疗的潜在效用 机会性播散性霉菌病和分枝杆菌病。 获得性免疫缺陷综合症(AIDS)的特征是 在免疫系统中表现为严重的 机会性感染。这类感染的治疗往往不够充分。 原因多种多样，包括缺乏有效的抗菌剂 心理治疗。 从历史上看，大多数细菌感染和局部真菌感染 已经得到了有效的治疗，使用的是众多临床可用的 抗生素。然而，需要新的、更有效和毒性更低的 治疗播散性真菌和分枝杆菌的抗生素 鉴于严重的毒性和失败，感染是显而易见的 当前可用代理的速率。新抗生素的发现 在过去成功地主要依靠孤立的 来自自然来源的代理。这种方法的主要优势是 对现有试剂进行化学合成或修饰的可能性 识别具有完全不同化学结构的新原型药物， 因此，发生类似毒性、交叉耐药和 行动机制。尽管微生物传统上被用作 新抗生素的主要来源，最近的研究表明 高等植物也是许多多样化和新奇植物的来源 抗菌剂。 该项目的目标是确定艾滋病相关抗生素的原型 01，将通过初步的体外抗真菌评价来完成 以及高等植物提取物的抗分枝杆菌活性。种 表现出良好活性的提取物将被分级和提纯，使用 一个以生物化验为导向的计划。这种方法确保了相对较少的 将时间和精力浪费在分离非活性物质上。纯正 显著最低抑菌浓度(MIC)活性化合物 并且在体外对哺乳动物细胞的细胞毒性相对较低 在已建立的播散性动物模型中评估体内疗效 真菌病和分枝杆菌病的潜在临床意义 实用程序。

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.