Mycobacterial trehalose metabolism as drug targets

目标：本提案的总体目标是更好地理解利用和 分枝杆菌中海藻糖的再循环。 二糖海藻糖对于分枝杆菌生理学的多个方面是重要的，并且已经被 显示出对活力至关重要，因为是导致海藻糖的下游利用途径 单菌酸盐生产和出口。用于构建外膜的海藻糖的再循环是 对M来说很重要。结核病毒力，并用于延长在结核病中具有各种作用的α-葡聚糖。 细菌。本研究项目有2个与海藻糖代谢相关的独立部分。第一 本研究的一部分旨在开发新型化合物，抑制三种酶的活性。 抗原85复合物。其次，我们将利用我们目前对GlgE蛋白结构的了解， 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。以来 GlgE的抑制促进M.结核病，改善目前的抑制剂将 大大提高了我们治疗结核病能力。预计这项研究的结果将扩大 可用M.结核病药物包括靶向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.