Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells.
Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells.
复制标题
增强的外排活性促进休眠细菌细胞的药物耐受性
DOI：
10.1016/j.molcel.2016.03.035
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发表时间：
2016-04-21
期刊：
影响因子：
16
通讯作者：
Bai F
中科院分区：
文献类型：
--
作者：
Pu Y;Zhao Z;Li Y;Zou J;Ma Q;Zhao Y;Ke Y;Zhu Y;Chen H;Baker MAB;Ge H;Sun Y;Xie XS;Bai F
基因表达的自然变异为同基因细菌群体中出现多种表型提供了机制。特别是，一个被称为持久性的亚组显示出对抗生素的高耐受性。以前，它们的形成被归因于细胞休眠。在这里，我们证明了细菌持留菌，在β-内酰胺抗生素治疗下，由于增强的外排活性，显示出较少的细胞质药物积累。一致的是，许多多药物外排基因，特别是中心组分TolC，在持久者中显示出更高的表达。延时成像和诱变研究进一步建立了tolC表达和细菌持久性之间的正相关性。外排系统的关键作用，在多个生物途径参与persister形成，表明persisters实现积极防御抗生素之前，通过休眠的被动防御。最后，外排抑制剂和抗生素一起有效地减弱持续存在的形成，这表明了靶向药物耐受性的组合策略。作为增加的外排率的直接结果，Persisters积累较少的抗生素，Persisters显示出更高的外排相关基因表达，tolC的高表达对促进Persisters形成至关重要。证明细菌持留菌除了生理静止外还表现出增强的外排活性，这是确保其在抗生素攻击下存活的双重保险策略。
Natural variations in gene expression provide a mechanism for multiple phenotypes to arise in an isogenic bacterial population. In particular, a sub-group termed persisters show high tolerance to antibiotics. Previously, their formation has been attributed to cell dormancy. Here we demonstrate that bacterial persisters, under β-lactam antibiotic treatment, show less cytoplasmic drug accumulation as a result of enhanced efflux activity. Consistently, a number of multi-drug efflux genes, particularly the central component TolC, show higher expression in persisters. Time-lapse imaging and mutagenesis studies further establish a positive correlation between tolC expression and bacterial persistence. The key role of efflux systems, among multiple biological pathways involved in persister formation, indicates that persisters implement a positive defense against antibiotics prior to a passive defense via dormancy. Finally, efflux inhibitors and antibiotics together effectively attenuate persister formation, suggesting a combination strategy to target drug tolerance. Persisters accumulate fewer antibiotics as a direct result of increased efflux rate Persisters show higher expression of efflux-associated genes High expression of tolC is critical to promote persister formation Persisters combine active efflux and passive dormancy to survive antibiotic attack By using in vivo fluorescent imaging and next-generation sequencing, Pu et al. demonstrate that bacterial persisters exhibit enhanced efflux activity in addition to physiological quiescence, a double insurance strategy to ensure its survival under antibiotic attack.