进入休眠或休眠样生理状态是细菌应对环境胁迫、逃避宿主免疫杀伤以及耐受药物杀菌的生存策略。代谢调控是细菌建立和维持休眠状态的关键，然而目前对休眠细菌的独特代谢机制还缺乏系统认识。我们前期研究揭示清除氧化型嘧啶核苷酸是稳定期分枝杆菌维护基因组稳定性和耐受药物杀菌的重要机制。近期，我们进一步发现嘧啶核苷酸代谢参与分枝杆菌休眠调控，并揭示嘧啶核苷酸代谢紊乱导致全局代谢及休眠/复苏调控发生显著变化。据此，我们提出嘧啶核苷酸代谢稳态是分枝杆菌建立休眠代谢的调控节点，计划在本研究中系统解析嘧啶核苷酸合成途径及步骤在分枝杆菌休眠调控中的作用，并利用代谢组、转录组及遗传互作等方法进一步刻画休眠过程中分枝杆菌维持嘧啶核苷酸稳态的协同代谢机制、揭示嘧啶核苷酸代谢影响分枝杆菌休眠的调控网络与生理机制。该研究将从核苷酸代谢角度深入解析分枝杆菌休眠调控及环境适应性机制，还将为持续性感染疾病的干预策略开发提供新的方向。

Many bacteria can weather the period of environmental stresses by entering a dormant or nongrowing physiological state. Recent studies demonstrated that some pathogenic bacteria could also use this strategy to tolerate both immune insults and prolonged antibiotic exposure, resulting in persistent infections. However, our knowledge of the unique metabolism and its regulation with respect to bacterial dormant state remains elusive. Our previous studies demonstrated that elimination of oxidative damaged dCTP via MazG plays a crucial role in genome maintenance and antibiotic tolerance in stationary-phase mycobacteria (PLoS Pathogens, 2013, 9: e1003814; PNAS, 2018, 115(9), 2210–2215). Our recent study established that pyrimidine nucleotide metabolism plays a critical role for mycobacteria to maintain dormant state under hypoxic and starvation conditions. Moreover, we provided evidence that the dysfunction of pyrimidine metabolism affects global metabolic state and the dormancy/resuscitation regulation pathways. Together, these results suggest that the homeostasis of pyrimidine nucleotide is a regulatory checkpoint during mycobacterial adaptation to nongrowing state (Emerging Microbes & Infection, 2019, 8(1): 40-44). In this project, we plan to dissect the role of pyrimidine synthesis pathways/steps in regulation of mycobacterial dormancy, and perform metabolic, transcriptomic and genetic interaction studies to figure out the mechanisms underlying the maintenance of pyrimidine nucleotide pool as well as its regulatory network that determines the physiology of mycobacterial dormancy. This study will not only shed light on the mechanisms about the regulation of mycobacterial dormancy and microbial adaptation, but also provide new direction for the development of novel intervention strategies for persistent infections.