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。耐药菌的流行加剧了结核的疫情，耐药机制不清阻碍了诊断开发和药物研制。因此，阐明耐药的分子机理，会为诊断和药物的开发提供理论依据。在几十年的探索中，传统的研究方法并不能完全揭示结核分枝杆菌耐药机理，需要新理念和新思路。最新的研究表明，细菌的耐药与活性氧的平衡有着重要的作用。我们认为活性氧稳态调节在结核分枝杆菌耐异烟肼中起着重要的作用，异烟肼是治疗结核的一线药物，其药物效果与细菌体内的氧化还原状态相关。我们的前期实验通过定向诱变进化筛选获得了一系列抗H2O2的突变体，初步鉴定抗H2O2与异烟肼的敏感性一致；我们将以此为基础发掘新的与耐异烟肼相关的关键基因，并利用这些候选基因，通过饵蛋白Pull-down和质谱等方法建立耐异烟肼蛋白群及相关通路，获得新的耐药相关基因和途径。我们的研究将为开发、准确的分子诊断技术和药物的发现提供理论基础。

Tuberculosis, caused by the pathogen Mycobacterium tuberculosis (Mtb), remains a public health threat and the prevalence of multi-drug resistant Mtb increases the threat. Fast, accuracy of clinical diagnosis of multi-drug resistant Mtb is urgently required for making right choices of therapy regiment, but the development of it is arrested due to the short of scientific basis. Isoniazid (INH) is an important, first-line antimycobacterial prodrug and its drug efficacy might influence by intracellular redox status. The known mutation sites in INH-tolerant Mtb are poor correlation to the INH-resistance, thus making it difficult to diagnose INH-tolerant in Mtb. This phenomenon suggests that mutations that confer INH-tolerance are to be identified. We reasoned that the genes involved to detoxify harmful reactive oxygen species of Mtb might also affect INH efficacy. In prelimiary experiment, We got several mutants with different level of hydrogen peroxide-resistance, respectively and we plan to identify the possible key candidates how to maintain redox balance under various hydrogen peroxide stress and possible the mechanisms involved into isonizid tolerance by using various methods including genetic and biochemical approaches. The knowledge should lead to novel strategies to develop new, accurate diagnosis methods.