GLYCOPEPTIDOLIPID BIOSYNTHESIS IN AVIUM COMPLEX

获得性免疫缺陷综合征的临床处理 (艾滋病)由于机会性感染而更加困难， 其中更严重的是涉及 鸟分枝杆菌复合体。因为航空分枝杆菌的成员 复合体对大多数抗分枝杆菌药物、疗法具有抗药性 通常涉及4-6种药物，预后较差。因为 糖肽脂类抗原(GPL)在人体内的战略定位 细胞壁和它们是M。 Avium复合体，抑制GPL的生物合成应导致 治疗由这些微生物引起的感染的选择性手段。 这个实验室以前的研究已经导致分离出 禽类丛枝杆菌复合变异体的研究进展 放射性标记技术可用于研究 GPL组分和相关前体的生物合成。这个 这项研究建议的长期目标是调查 GPL的生物合成途径在代谢鉴定中的作用 选择性抗菌活性的靶标。最直接的 目标将是确定GPL中的潜在前体 在无细胞系统中生物合成并利用这些前体 进一步描述了GPL组分的生物合成途径。 将采取两种方法来确定潜在的前兆。 在第一种方法中，分枝杆菌将用以下药物治疗 有可能抑制GPL的生物合成和放射性标记 将使用技术来识别伴随的累积 放射性标记的前体。在第二种方法中，粗糙群 缺乏完成GPL合成能力的变体 成分但包含GPL合成的初始产物，还将 被用来确定潜在的前体。潜能的能力 参与GPL生物合成的前体将通过以下方式确认 使用已开发的用于体外研究的无细胞系统 GPL组分的生物合成。一旦前兆已经被 确认后，将利用无细胞系统进行检查 特异性抑制物对GPL生物合成的影响。这些 研究应该最终导致关键酶的鉴定 在GPL的生物合成途径中，从而使其有可能发展 禽支原体复合体的选择性抗菌治疗 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.