GLYCOPEPTIDOLIPID BIOSYNTHESIS IN AVIUM COMPLEX

获得性免疫缺陷综合征的临床治疗 （艾滋病）由于机会性感染而更加困难， 其中更严重的是涉及成员的事件 鸟分枝杆菌复合体。 因为 M. avium 的成员 复合物对大多数抗分枝杆菌药物、治疗具有耐药性 通常涉及4-6种药物，预后较差。 因为 糖肽脂抗原（GPL）的战略位置 细胞壁以及它们是 M 成员所独有的事实。 avium 复合物，抑制 GPL 生物合成应导致 治疗由这些生物体引起的感染的选择性方法。 该实验室先前的研究已分离出 粗糙菌落 M. avium 复合体变种和开发 放射性标记技术可用于研究 GPL 成分和相关前体的生物合成。 的 本研究计划的长期目标是调查 GPL 的生物合成途径，旨在鉴定代谢 选择性抗菌活性的目标。 即时的 目标是确定 GPL 的潜在先驱 生物合成并在无细胞系统中利用这些前体 进一步描绘GPL成分的生物合成途径。 将采取两种方法来识别潜在的前体。 在第一种方法中，将使用以下药物治疗分枝杆菌： 具有抑制 GPL 生物合成和放射性标记的潜力 技术将用于识别伴随的积累 放射性标记的前体。 第二种方法，粗集落 变种，缺乏完成GPL合成的能力 成分但包含 GPL 合成的初始产物，也将 用于识别潜在的前体。 潜力的能力 参与 GPL 生物合成的前体将由 使用为体外研究而开发的无细胞系统 GPL 成分的生物合成。 一旦前体已经 确认后，将使用无细胞系统来检查 特定抑制剂对 GPL 生物合成的影响。 这些 研究最终应导致关键酶的鉴定 在 GPL 生物合成途径中，从而使开发成为可能 用于治疗鸟分枝杆菌复合体的选择性抗菌疗法 感染。

The clinical management of acquired immune deficiency syndrome (AIDS) is more difficult because of opportunistic infections, the more serious of which are those involving members of the Mycobacterium avium complex. Because members of the M. avium complex are resistant to most antimycobacterial drugs, therapy usually involves 4-6 drugs and prognosis is poor. Because of the strategic location of the glycopeptidolipid antigens (GPL) in the cell wall and the fact that they are unique to members of the M. avium complex, inhibition of GPL biosynthesis should lead to a selective means of treating infections caused by these organisms. Previous studies in this laboratory have lead to the isolation of rough-colony M. avium complex variants and the development of radiolabeling techniques which can be used to study the biosynthesis of the GPL components and related precursors. The long term objective of this research proposal is to investigate the biosynthetic pathway of the GPL in an effort to identify metabolic targets for selective antimicrobial activity. The immediate objective will be to identify potential precursors in GPL biosynthesis and utilize those precursors in a cell-free system to further delineate the biosynthetic pathway of the GPL components. Two approaches will be taken to identify the potential precursors. In the first approach mycobacteria will be treated with drugs which have the potential to inhibit GPL biosynthesis and radiolabeling techniques will be used to identify concomitant accumulation of radiolabeled precursors. In the second approach, rough-colony variants, which lack the ability to complete the synthesis of GPL components but contain initial products of GPL synthesis, will also be used to identify potential precursors. Ability of the potential precursors to participate in GPL biosynthesis will be confirmed by using a cell-free system which has been developed to study in vitro biosynthesis of GPL components. Once the precursors have been confirmed, then the cell-free system will be utilized to examine the effect of specific inhibitors on GPL biosynthesis. These studies should eventually lead to the identification of key enzymes in the GPL biosynthetic pathway, thus making it possible to develop selective antimicrobial therapy for treating M. avium complex infections.