Mycobacterial trehalose metabolism as drug targets

目标：本提案的总体目标是更好地了解利用和 分枝杆菌中海藻糖的循环利用。 二糖海藻糖对分枝杆菌生理学的多个方面都很重要，一直以来 海藻糖的下游利用途径被证明是生存所必需的 单菌酯的生产和出口。回收用于构建外膜的海藻糖是 对结核分枝杆菌的毒力很重要，被用来延长a-葡聚糖，它在 细菌。本研究项目包括与海藻糖代谢相关的两个独立部分。第一 这项研究的一部分旨在开发新的化合物类别，以抑制细胞的三种酶 抗原85复合体。其次，我们将利用我们目前对GlgE蛋白质结构的知识来开发 第二代抑制剂和用于评估这些抑制剂的抑制剂活性的改进工具。自.以来 抑制GlgE促进对结核分枝杆菌的快速杀灭，改进目前的抑制剂Will 大大提高了我们治疗结核病的能力。预计从这项研究中获得的结果将扩大 现有的结核分枝杆菌药物包括针对海藻糖生物合成和利用的化合物。

Goal: The overarching goal of this proposal is to better understand key steps in the utilization and recycling of trehalose in mycobacteria. The disaccharide trehalose is important for multiple aspects of mycobacterial physiology and has been shown to be essential for viability as is the downstream utilization pathway that leads to trehalose monomycolate production and export. Recycling of the trehalose used to build the outer membrane is important for M. tuberculosis virulence and is used to extend a-glucans that have various roles in the bacterium. This research project possesses 2 separate portions related to trehalose metabolism. The first portion of this study aims to develop novel classes of compounds that inhibit the three enzymes of the Antigen 85 Complex. Second, we will use our current knowledge of GlgE protein structure to develop second-generation inhibitors and improved tools for assessing the inhibitor activity of these inhibitors. Since inhibition of GlgE promotes rapid killing of M. tuberculosis, improving upon the current inhibitors will significantly advance our ability to treat TB. It is expected that results obtained from this study will extend the available M. tuberculosis drugs to include compounds that target trehalose biosynthesis and utilization.