氧气在大肠杆菌稳定期持留菌形成中的作用机制研究

持留菌是一种对抗生素不敏感的细菌，其本身并没有发生遗传物质变化，仅由于基因表达的变化形成一种能够在高浓度抗生素处理下依然存活的状态，在去掉抗生素之后能够重新恢复。由于持留菌的这种抗生素杀不死的特性，是造成一些感染性疾病治疗时间长、反复发作的重要原因，同时还会提高细菌产生耐药突变的风险。细菌进入稳定期是持留菌形成的最主要因素，但目前已经发现的持留菌形成机制并不能解释该现象。我们的前期研究发现，在排除了其它影响之后，稳定期的细菌密度降低之后会极大的增强抗生素的杀菌活性，RNAseq结果表明稀释之后细菌内部产生了大量的过氧化氢，而过氧化氢的产生与氧浓度升高相关，表明氧可能在稳定期细菌持留菌形成中起着关键的作用，本项目将对其作用机制进行深入研究，有望发现持留菌形成的重要机制，为开发能够持留菌药物，缩短感染性疾病的治疗时间奠定基础。

Persisters are a fraction of bacteria that can survive high dose of antibiotics due to epigenetic changes but not genetic mutations. Because the persisters can survive the antibiotic treatments and grow again when the antibiotics are removed, they are considered an important cause of prolonged treatment and relapse for various persistent bacterial infections. Persistence also could promote the generation of genetic resistance. Although significant progress has been made in our understanding of mechanisms of persister formation, the most significant observation of persister formation when bacteria enter stationary phase cannot yet be explained by our current understanding of persister mechanisms. In our recent studies, we made the very interesting observation that, after excluding other possible factors such as exhaustion of nutrients and toxic substance buildup, the cell density in stationary phase culture greatly affects the persistence phenomenon. RNAseq analysis showed that many genes related to hydrogen peroxide production were highly expressed when the stationary phase E.coli were diluted in its own supernatant. We found that intracellular hydrogen peroxide was significantly elevated at higher dissolved oxygen level, indicating that oxygen and hydrogen peroxide may play an important role in persister formation. Further investigation of the mechanisms of how oxygen and peroxide control the persister formation will pave the way to develop more effective drugs targeting persisters for more effective treatment of persistent bacterial infections.