结核分枝杆菌药物外排泵Rv1457-Rv1458的结构与功能研究

结核病（Tuberculosis, TB）是全球致死人数最多的传染性疾病，是由结核分枝杆菌（Mycobacterium tuberculosis, MTB）引发的。耐药结核的出现成为目前抗结核工作面临的最大问题。外排泵的过表达是赋予MTB耐药性的主要原因之一。ABC 转运蛋白超家族生理功能复杂，与MTB的耐药性紧密相关，是存在于MTB 的主要外排泵系统。Rv1457-Rv1458是结核分枝杆菌生长必需的基因，被鉴定为ABC转运蛋白类型的药物外排泵。在一些临床分离的耐药MTB菌株中，Rv1457-Rv1458都有过量表达。但其参与的生理过程以及所排抗生素类型仍旧未知。本项目拟利用单颗粒冷冻电镜的方法获得Rv1457-Rv1458的三维结构，探究其底物转运机制和药物外排机制，为基于Rv1457-Rv1458这一潜在药靶的抗结核药物开发提供理论依据和结构基础。

Tuberculosis (TB) is the infectious disease resulting the highest mortality worldwide and is caused by Mycobacterium tuberculosis (MTB). The emergence of drug-resistant tuberculosis has become the biggest problem for the current anti-tuberculosis work. Overexpression of the efflux pump is one of the main reasons that confer MTB resistance. The ABC transporter superfamily is multifunctional and is closely related to the drug resistance of MTB. It is the main efflux pump system that exists in MTB. Rv1457c-Rv1458c are essential genes for the growth of MTB and is a drug efflux pump belonging to the ABC transporter family. In some clinically isolated drug-resistant MTB strains, the expression of Rv1457c-Rv1458c are significantly increased. However, the physiological process Rv1457-Rv1458 is involved and the types of antibiotics it exports remains unknown. This research will aim to obtain the three-dimensional structure of Rv1457-Rv1458 by single particle cryo-EM, explore its substrate transport mechanism and drug efflux mechanism. This study will lay a solid foundation for the development of anti-tuberculosis drugs based on Rv1457-Rv1458 as a potential drug target.