结核病是由结核分枝杆菌引起的、导致人类死亡最多的传染病之一。结核菌重要特征是感染人体可以潜伏存在，细菌处于不分裂的状态，在此状态下为生理性耐药，临床表现对抗生素不敏感。结核菌的潜伏感染和耐药是结核防治的难题，对结核菌耐药机制和潜伏感染深入研究为获得药物筛选的靶标及筛选模型的建立提供科学理论依据。异烟肼是治疗活动性结核和干扰潜伏感染的重要药物，我们前期研究显示潜伏相关蛋白结核广谱胁迫蛋白Rv1996与异烟肼的耐药性相关，我们将以此为基础1）利用遗传学、生物化学等技术阐释Rv1996与KatG的作用方式及对异烟肼抗性的影响；2）通过体内垂钓、定量质谱组学及生化分析，鉴定以Rv1996为核心的调控异烟肼抗性的关键蛋白。我们希望本项目能够揭示以Rv1996为核心的影响KatG及异烟肼抗性的关键蛋白及相关通路，获得结核菌耐异烟肼的新机制，为开发准确的分子诊断技术和研发高效的抗结核药物提供理论基础。

Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis, is one of the most serious infectious diseases in the world and caused millions of people deaths per year. M. tuberculosis, as an intracellular pathogen, has evolved special mechanisms of latency in host cells protecting itself from clearance. The latent M. tuberculosis is a potential source of development of active TB patients. But the related mechanisms such as the bacilli how to switch to latent status and how to resuscitate have not been fully explored. Moreover, the prevalence drug-resistant M. tuberculosis worsens the situation. Fast, accuracy of clinical diagnosis of the physiological status in patients and the antibiotic resistance of M. tuberculosis is urgently required for selection of therapy regiment, but the development of it is arrested due to being lack of scientific basis. Isoniazid (INH) is an important first-line drug for the treatment of active and latent TB. Recently studies showed that INH resistance is growth phase-dependent. But phenotypic resistance to INH is poorly understood. Our previous study showed that overexpresses the latent protein universal stress protein (USP) Rv1996 increased susceptibility to INH compared with the wild-type strain. Following our previous studies, we are going to 1) define how Rv1996 regulate KatG by using genetics and biochemical approaches; 2) explore the pathway of Rv1996 mediated INH resistance through KatG. Our studies will give an insight in the development of new diagnosis methods and providing the potential drug selection targets.