结核杆菌（MTB）是引起结核病（TB）的罪魁祸首，杀灭耐药和潜伏MTB是控制结核病的关键，开发新型药物对于控制耐药结核传播和潜伏菌复发至关重要。药物研发瓶颈在于靶点的不确定性，而靶点的药理学验证才是确证靶点真实性的首要必备条件。丙嗪酰胺（PZA）是一个独特抗结核药物，具有抑制潜伏结核杆菌活性并是结核病（敏感和耐药）治疗中唯一不可替代的药物。反式翻译过程关键蛋白RpsA是我们前期发现的PZA作用靶点（Science，2011），且通过结构解析蛋白与药物分子作用模式而明确的新型抗结核潜在靶点（Mol. Micro.2015）。在此靶点基础上，筛选到具有抗结核杆菌活性的化合物，本项目拟继续通过活性化合物对反式翻译过程及RpsA影响及作用机制的深入研究来揭示RpsA及反式翻译过程作为新型抗结核靶点的真实可靠性。研究成果为发现新型抗结核药物靶标提供基础，对开发源头创新的抗结核杆菌药物有着重要意义。

The global control and management of tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and remains a major health threat. The global control and management of tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and remains a major health threat. The success of Mtb as a pathogen is partly due to its ability to persist in host microenvironments. Control of TB is faced with the formidable challenge of worsening scenarios of drug-resistance and persistence of Mtb. Identification of new mechanisms of drugs is very important to control transmission of Mtb and reactivation from latent tuberculosis. However, lack of novel and validated drug targets limits the progress of drug research and development. Pharmacological validation of a potential target is an important prerequisite for drug discovery, and few such targets are known in Mtb..Pyrazinamide (PZA) is a unique first-line drug used for the treatment of TB. It plays a key role in killing non-replicating persisters that other TB drugs fail to kill, which makes it an essential drug for inclusion in any drug combinations for treating drug-susceptible and drug resistant TB such as multidrug-resistant TB. RpsA (ribosomal protein S1), which is involved in process of trans-translation, was identified as a target of PZA based on its binding activity to pyrazinoic acid (POA), the active form of PZA in our previous research (Science, 2011). In addition, we reported the crystal structures of the C-terminal domain of RpsA of Mtb and its complex with POA, as well as the corresponding domains of two RpsA variants that are associated with PZA resistance (Mol. Micro.2015). The pharmacological validation of PZA target proposed that the trans-translation machinery, in particular, the RpsA protein maybe an excellent target for the development of novel antituberculosis. .On the basis of structural data, screening was performed in a search for novel binding molecules of RpsA, and several compounds with antituberculosis activity were screened in vitro. In this project, the activity of compounds against active Mtb and persisters will be further evaluated. In order to validate the reliability of RpsA and trans-translation process as the novel targets against TB, a series experiments on interaction between active compounds and RpsA will be performed. Moreover, effects of compounds on tmRNA binding activities of RpsA proteins and on trans-translation progress will be tested. Our studies may uncover RpsA and trans-translation process as novel targets for chemotherapeutic intervention. Screening of inhibitors of trans-translation progress may be an attractive strategy for development of novel antibiotics against TB.