全球当前的耐药结核病尤其是耐多药和广泛耐药结核病疫情极其严峻。由于可有效治疗耐药结核病的药物种类有限，急需开发基于新靶标的抗结核药物。在宿主中长期存活和进化的结核分枝杆菌，必然与宿主细胞进行密切的相互作用和信息交流，因此深入研究其在宿主巨噬细胞中存活的分子机制对于阐明结核病的致病机理以及探寻结核分枝杆菌新药靶具重要意义。研究表明：结核分枝杆菌中有11个真核样丝氨酸/苏氨酸蛋白激酶，其中的PknG可分泌性到巨噬细胞中并且是结核分枝杆菌胞内存活所必需的，因此它可能是一种较为理想的结核分枝杆菌新药靶，但其促进结核分枝杆菌胞内存活的分子机制尚未明确。在本研究中，我们拟综合应用生物化学与分子生物学、细胞生物学和免疫学等方法和技术深入探寻PknG促进结核分枝杆菌在宿主巨噬细胞内存活的分子机制。该研究将有助于阐明结核分枝杆菌潜伏感染及致病的分子机制，同时还可能为抗结核新药研发和优化提供新的思路和和靶标。

The global situation of drug-resistant tuberculosis (TB), especially multidrug-resistant and extensively drug-resistant TB is very severe. With limited number of effective drugs available for the treatment of drug-resistant TB cases, more intensive efforts are urgently needed for the development of anti-TB drugs based on novel drug targets. In order to survive and evolve in the host macrophages for long-term, M. tuberculosis needs to interact and exchange information with host macrophages frequently. Thus it is of great importance to investigate the molecular mechanisms underlying the intracellular survival of M. tuberculosis to gain a better understanding of the pathogenesis of TB as well as to identify novel anti-TB drug targets. Previous studies have shown that there are 11 eukaryotic serine-threonine kinases within M. tuberculosis, among which the PknG is secreted into host macrophages and is required for the intracellular survival of M. tuberculosis, thus it is a potently ideal novel anti-TB drug target, but the mechanisms by which PknG promotes the intracellular survival of M. tuberculosis are largely unclear. In this project, we will apply multiple methodologies and techniques of biochemistry and molecular biology, cell biology, and immunology into the investigation of molecular mechanisms underlying PknG promoted intracellular survival of M. tuberculosis. This project would shed light on the molecular mechanisms of latent infection and pathogenesis of M. tuberculosis. In addition, it would provide knowledge and novel targets for the development and optimization of more effective anti-TB drugs.