结核分枝杆菌是引起结核病的病原体。由于多重耐药菌株和广泛耐药菌株的出现，现有的抗结核药物不能有效地治愈结核病，使人类健康受到严重的危害。因此，急需研发新型抗结核药物。细胞壁是维持结核分枝杆菌生存的重要结构，一旦细胞壁遭到破坏，细菌将会死亡。UDP-N-乙酰葡糖胺是细胞壁多糖合成的糖基供体和前体分子，双功能酶GlmU催化UDP-N-乙酰葡糖胺生物合成途径的最后两步反应。我们敲除glmU基因后，发现细菌细胞壁结构改变，细菌裂解、死亡。因此，GlmU是抗结核新药的理想靶标。我们通过高通量筛选得到5种不同分子结构的GlmU乙酰基转移酶抑制剂。本课题将确定5种抑制剂对GlmU乙酰基转移酶的抑制作用类型，利用分子对接及基因定点突变方法揭示抑制剂与GlmU酶相互作用的特点；评价抑制剂对结核分枝杆菌的抑菌效果并探讨抑制剂对细胞壁糖组分及细胞形态和结构的影响。本研究结果为发现新型抗结核药物提供理论依据。

Mycobacterium tuberculosis is a pathogen to cause tuberculosis. Due to the emergence of multi-drug-resistant strains and extensively drug-resistant strains, the existing anti-tuberculosis drugs are unable to cure tuberculosis effectively. Tuberculosis is serious threat to the human health. Therefore, it is urgent for us to develop new anti-tuberculosis drugs. The cell wall is an important structure for the survival of Mycobacterium tuberculosis. The bacteria will die once the cell wall is damaged. UDP-N-acetyl glucosamine is the glycosyl donor and precursor in the biosynthesis of cell wall polysaccharide. Bifunctional enzyme GlmU catalyzes the last two steps of reactions in the formation of UDP-N-acetyl glucosamine. The knockout of glmU gene caused mycobacterial lysis and death in our previous studies. Therefore, GlmU is an ideal target for new anti-tuberculosis drugs. We acquired five kinds of inhibitors for GlmU acetyl transferase by high throughput screening compound libraries from different sources. In this study we will investigate the action modes of five inhibitors on GlmU acetyl transferase and understand the interaction mechanism between the each inhibitor and GlmU enzyme by using molecular docking and site-specific mutagenesis methods. We will evaluate the inhibitory activities of GlmU inhibitors to growth of Mycobacterium tuberculosis. We also investigate the effects of five inhibitors on composition of polysaccharide in the cell wall and on the morphology and structure of Mycobacterium tuberculosis. The results from this study will provide a theoretical basis for the discovery of new anti-tuberculosis drugs.