结核分支杆菌ESX-5分泌系统的结构与分泌机制的研究

结核病，由结核分支杆菌感染引起的传染性疾病，是目前世界上致死率最高、传播范围最广的细菌性疾病。在过去的200年里，结核病已经夺走了超过10亿人的生命。虽然结核病可以通过一线临床药物结核二线临床药物治疗，但是耐药性仍是一个巨大的威胁。由于耐多药菌株(MDR-TB)和广泛耐药菌株(XDR-TB)的出现,使得现有药物的治疗几乎失效。因此,寻找新的药物靶点以及研究全新作用机制的强力抗结核药物已经成为迫在眉睫的重要任务。结核分支杆菌VII型分泌系统作为一个新型的重要药物靶点位于细胞膜上能够分泌一系列毒力蛋白，代谢产物，细胞壁组分以及摄取营养物质,从而维持其结构的完整和生理的稳态。迄今为止,其三维结构和催化机制尚不清楚。运用结构生物学手段确定参与ESX系统的组分，并解析其蛋白复合物的高分辨率结构，鉴定不同组分的相互作用模式，阐明ESX系统转运底物的分子机制，为设计新型的抗结核药物奠定坚实的分子基础。

Tuberculosis caused by infection with Mycobacterium tuberculosis, is one of the most lethal and wild-spreading contagious disease worldwide. Over the past 200 years, TB has claimed the lives of more than one billion people---more deaths than from malaria, influenza, smallpox, HIV/AIDS, cholera, and plague combined. Although TB can be treated by first-line drugs combined with second-line drugs, drug resistance is a continued threat. The emergence of multidrug-resistant (MDR) TB and extensively drug-resistant (XDR) TB has intensified the need of new anti-tuberculosis drug by discovering new potential drug target and mechanism of drug action. ESX systems (VII type secretion system), a type of novel and promising drug target, function as specialized secretion systems locating at cell membrane that enable the transport of virulence factors, metabolite and secreted effector protein across the complex and thick mycobacterial cell envelope, leading to structural integrity and physiological homeostasis. To date, the precise structure and secretion mechanism of ESX system remains mysterious. Clarifying components of ESX system and determining atomic-resolution structure by structural biology methodology can contribute to identify interactive pattern of core components of ESX system, elucidate the molecular mechanism of substrate secretion which will lay a solid foundation for designing innovative anti-TB drugs.