Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
Nat Chem Biol. 2010 May;6(5):376-84. doi: 10.1038/nchembio.340. Epub 2010 Mar 21.
New chemotherapeutics are urgently required to control the tuberculosis pandemic. We describe a new pathway from trehalose to alpha-glucan in Mycobacterium tuberculosis comprising four enzymatic steps mediated by TreS, Pep2, GlgE (which has been identified as a maltosyltransferase that uses maltose 1-phosphate) and GlgB. Using traditional and chemical reverse genetics, we show that GlgE inactivation causes rapid death of M. tuberculosis in vitro and in mice through a self-poisoning accumulation of maltose 1-phosphate. Poisoning elicits pleiotropic phosphosugar-induced stress responses promoted by a self-amplifying feedback loop where trehalose-forming enzymes are upregulated. Moreover, the pathway from trehalose to alpha-glucan exhibited a synthetic lethal interaction with the glucosyltransferase Rv3032, which is involved in biosynthesis of polymethylated alpha-glucans, because key enzymes in each pathway could not be simultaneously inactivated. The unique combination of maltose 1-phosphate toxicity and gene essentiality within a synthetic lethal pathway validates GlgE as a distinct potential drug target that exploits new synergistic mechanisms to induce death in M. tuberculosis.
急需新的化疗药物来控制结核病大流行。我们描述了结核分枝杆菌中从海藻糖到α-葡聚糖的新途径，该途径包含由TreS、Pep2、GlgE（已被鉴定为使用麦芽糖 1-磷酸的麦芽糖基转移酶）和 GlgB 介导的四个酶促步骤。通过传统和化学反向遗传学，我们表明 GlgE 失活会导致结核分枝杆菌在体外和小鼠中迅速死亡，这是通过麦芽糖 1-磷酸的自我中毒积累引起的。中毒引发了由自我放大反馈环促进的多磷酸糖诱导的应激反应，其中海藻糖形成酶上调。此外，从海藻糖到α-葡聚糖的途径与参与多甲基化α-葡聚糖生物合成的葡糖基转移酶 Rv3032 表现出合成致死相互作用，因为每个途径中的关键酶不能同时失活。麦芽糖 1-磷酸毒性和基因必需性在合成致死途径中的独特组合验证了 GlgE 作为一种独特的潜在药物靶点的合理性，它利用新的协同机制在结核分枝杆菌中诱导死亡。
