结核分枝杆菌感染引起的传染性疾病严重危害我国及全人类的身体健康。耐药结核菌的防治是世界性的难题。细菌与宿主相互作用界面做为靶点，是新的药物筛选策略。我们的前期研究显示分枝杆菌五肽重复序列蛋白MfpA不仅与DNA旋转酶相互作用影响喹诺酮药物抗性，还是一个分泌蛋白，影响细菌在宿主细胞中的存活。我们推测MfpA与宿主线粒体TOP2相互作用，促进结核菌在宿主体内的存活。本项目综合应用生化和分子生物学、细胞生物学等方法，从分子水平、细胞水平和动物水平，研究MfpA如何通过与宿主线粒体的DNA拓扑异构酶TOP2的相互作用，调控宿主线粒体基因组复制、转录，干扰线粒体活性的机制。进一步，建立细菌-宿主-药物模型，解析MfpA在药物干预下分枝杆菌感染宿主的影响，寻找药物处理下细菌与宿主的相互作用改变的规律。项目研究将增进结核分枝杆菌致病机制的认识及药物对感染宿主内病原菌的干预机制的理解。

Infectious diseases caused by Mycobacterium tuberculosis infection seriously endanger the health of all human beings. The prevention and treatment of drug-resistant tuberculosis is a worldwide problem. The interference of an interface between bacteria and host, regulating the body's immune system to improve the ability to kill invading bacteria, can effectively avoid the emergence of M. tuberculosis drug resistance. Our previous studies showed that the mycobacterial pentapeptide repeat protein MfpA not only affects the resistance of quinolone drugs but also a secreted protein, affecting the survival of mycobacteria in host cells. We speculate that MfpA may interact with host mitochondria topoisomerase TOP2, which dysregulates mitochondria activities and interferes with the host's immune signal , causing the survival of Mycobacterium tuberculosis in the host. In this project, we will study how MfpA regulates TOP2 enzyme activity, which interferes with mitochondria genome replication, transcription and leads to mitochondrial dysfunction, causing an aberrant immune response. Furthermore, we plan to use Mycobacterium marinum infected zebrafish to analyze the effects of MfpA on tuberculosis pathogenesis, as well as for drug interference. Our study will provide an insight into the understanding of the pathogenesis of Mycobacterium tuberculosis and the understanding of the intervention mechanism of the drug on the pathogens in the infected host.