School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), 1015 Lausanne, Switzerland.
Science. 2013 Jan 4;339(6115):91-5. doi: 10.1126/science.1229858.
Exposure of an isogenic bacterial population to a cidal antibiotic typically fails to eliminate a small fraction of refractory cells. Historically, fractional killing has been attributed to infrequently dividing or nondividing "persisters." Using microfluidic cultures and time-lapse microscopy, we found that Mycobacterium smegmatis persists by dividing in the presence of the drug isoniazid (INH). Although persistence in these studies was characterized by stable numbers of cells, this apparent stability was actually a dynamic state of balanced division and death. Single cells expressed catalase-peroxidase (KatG), which activates INH, in stochastic pulses that were negatively correlated with cell survival. These behaviors may reflect epigenetic effects, because KatG pulsing and death were correlated between sibling cells. Selection of lineages characterized by infrequent KatG pulsing could allow nonresponsive adaptation during prolonged drug exposure.
在将一种杀菌抗生素暴露于同源细菌种群时，通常无法消除一小部分耐药细胞。从历史上看，这种分数杀灭归因于不频繁分裂或不分裂的“持久细胞”。通过使用微流控培养和延时显微镜观察，我们发现分枝杆菌通过在药物异烟肼（INH）存在的情况下分裂而存活。尽管在这些研究中，持久性表现为细胞数量稳定，但这种明显的稳定性实际上是一种平衡分裂和死亡的动态状态。单个细胞以随机脉冲的形式表达过氧化氢酶过氧化物酶（KatG），该酶激活 INH，与细胞存活呈负相关。这些行为可能反映了表观遗传效应，因为 KatG 脉冲和死亡在兄弟姐妹细胞之间存在相关性。选择 KatG 脉冲不频繁的谱系可能会在长时间暴露于药物时允许非应答性适应。
