Cell Envelope Biogenesis in Mycobacterium tuberculosis

项目摘要 为了根除结核病，世界卫生组织建议将结核病相关死亡人数从 到2025年，每年从100万人减少到5万人。这95%的削减将无法通过目前的方案来实现。因此 消除结核病的战略计划强调开发针对致病细菌的新药， 结核分枝杆菌（Mtb）。因此，Mtb细胞包膜已经成为许多努力的目标，以寻找新的抗结核药物。 抗结核病治疗。然而，新靶点的发现和验证受到我们有限的 了解细胞膜是如何形成的。 酶，使菌膜脂质已被表征，但随后的脂质的机制， 掺入到菌膜中仍然不清楚。我们和其他人已经确定了一条途径， 所需的运输和合成的各种菌膜脂质。 基于我们已发表的工作和初步数据，我们假设脂蛋白LprG和膜 蛋白Rv 1410 c通过介导转运的关键步骤在菌膜生物合成中发挥广泛作用 脂质越过细胞质膜进入菌膜。为了测试这个模型，我们将继续 以下目标： (1)确定LprG和Rv 1410 c如何调节脂质转运到菌膜，以及（2）确定LprG和Rv 1410 c如何调节脂质转运到菌膜， LprG-Rv 1410 c调节向菌膜添加携带分枝菌酸的毒力因子。我们 创新是为了测试一种新的菌膜生物发生模型，为此，我们将利用我们的专业知识 在分枝杆菌学和脂质生物化学中，以实现我们理解脂质转运的长期目标 使菌膜形成并有助于毒性的过程。圆满完成 这些特定的目标将为我们理解一个与药物相关的途径提供重要的进展 在结核分枝杆菌细胞包膜中介导这些过程。

Project Summary To eradicate tuberculosis (TB), the World Health Organization has proposed reducing TB-related deaths from >1 million to just 50,000 per year by 2025. This 95% reduction will not be met by current programs. Thus, the strategic plan to eliminate TB emphasizes the development of new drugs against the causative bacterium, Mycobacterium tuberculosis (Mtb). The Mtb cell envelope has thus been the target of many efforts to find novel anti-TB therapeutics. However, discovery and validation of new targets is hampered by our limited understanding how the cell envelope is made. Enzymes that make mycomembrane lipids have been characterized, but the mechanism of subsequent lipid incorporation into the mycomembrane remains poorly defined. We and others have identified a pathway that is required for both the transport and the synthesis of diverse mycomembrane lipids. Based on our published work and preliminary data, we hypothesize that the lipoprotein LprG and membrane protein Rv1410c play a broad role in mycomembrane biogenesis by mediating a crucial step in transporting lipids beyond the cytoplasmic membrane and into the mycomembrane. To test this model, we will pursue the following aims: (1) Determine how LprG and Rv1410c regulate lipid transport to the mycomembrane and (2) Determine how LprG-Rv1410c regulates the addition of mycolic acid-bearing virulence factors to the mycomembrane. Our innovation is to test a novel model for mycomembrane biogenesis and to do so we will leverage our expertise in mycobacteriology and lipid biochemistry to achieve our long-term goal of understanding lipid transport processes that enable the mycomembrane to form and contribute to virulence. The successful completion of these Specific Aims will provide important advances in our understanding of a virulence-associated pathway that mediates these processes in the Mtb cell envelope.