异烟肼是治疗结核病的重要一线药物，而异烟肼耐药结核菌的不断增加是结核病防控的巨大挑战。因此解析异烟肼耐药机制是结核病防治的关键之一。我们前期蛋白组学研究表明蛋白质赖氨酸酰化修饰如乙酰化、琥珀酰化可能在结核菌耐药中发挥重要作用。Rv1151c是结核菌中负责蛋白质去乙酰化和去琥珀酰化的关键酶。预实验发现Rv1151c在异烟肼耐药的临床结核菌株中高表达，且过表达该基因的耻垢分枝杆菌对异烟肼耐受，提示Rv1151c参与结核菌异烟肼耐药，但其具体分子机制未知。本项目拟采用同源基因敲除、MIC测定、抑制剂联合杀菌等实验，探讨Rv1151c影响结核菌对异烟肼的敏感性；通过定量乙酰化及琥珀酰化组学、免疫共沉淀、定点突变等方法，探究Rv1151c对反应调控因子MprA去乙酰化和去琥珀酰化，进而下调过氧化物酶KatG表达水平介导结核菌异烟肼耐药的机理。这将为研发异烟肼增效剂和结核病临床治疗提供重要理论基础。

Isoniazid (INH) is an important first-line drug for the treatment of TB. INH resistance of Mycobacterium tuberculosis is an increasing problem in the treatment of tuberculosis (TB). Therefore, the identification of genes associated with INH resistance and understanding the molecular mechanism are of great significance on the clinical treatment of TB and the development of new drugs.Our previous studies had shown that protein lysine acylation including acetylation and succinylation may play an important role in mycobacterium antibiotic resistance. Rv1151c is the key enzyme responsible for deacetylation and desuccinylation. Our preliminary data demonstrate that Rv1151c gene is up-regulated in INH-resistant M. tuberculosis isolates, and the overexpression of Rv1151c in Mycobacterium smegmatis confers resistance to INH, however, the detailed mechanism is unclear. This project is to explore the influence of Rv1151c expression on the isoniazid sensitivity of mycobacterium by using homologous gene knock-out, MIC determination of antibiotics on solid and liquid medium, and killing curve, etc; to reveal the molecular mechanism of Rv1151c in regulating isoniazid resistance of mycobacterium throughdeacetylation and desuccinylation of the response regulator MprA by utilizing qPCR, quantitative acetylome and succinylome, co-immunoprecipitation, etc. This will provide a theoretical basis for clarifying drug resistance mechanism of Mycobacterium tuberculosis and the development of isoniazid synergist.