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，每年将达到100万至5万人。目前的计划无法满足这一95%的降幅。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，结核分枝杆菌细胞囊膜一直是许多人努力寻找新的 抗结核疗法。然而，新目标的发现和确认受到我们有限的限制 了解细胞包膜是如何形成的。 制造肌膜脂类的酶已经被表征，但随后的脂类的机制 结合到菌膜仍然是不明确的。我们和其他人已经确定了一条路径 这是运输和合成各种菌膜脂类所必需的。 根据我们已发表的工作和初步数据，我们假设脂蛋白LprG和膜 Rv1410c蛋白在菌膜生物发生中起重要作用 脂类越过细胞膜进入菌膜。为了测试这个模型，我们将继续 以下目标： (1)确定LprG和Rv1410c如何调节脂质向肌膜的运输；(2)确定如何 LprG-Rv1410c调节霉菌酸致病力因子在菌膜上的添加。我们的 创新是测试一种新的肌膜生物发生模型，为此，我们将利用我们的专业知识 在分枝杆菌学和脂类生物化学方面，以实现我们了解脂类运输的长期目标 使菌膜形成并促成毒力的过程。圆满完成 这些特定的目标将为我们理解毒力相关的途径提供重要的进展。 它在结核分枝杆菌细胞包膜中调节这些过程。

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.