Ranking of persister genes in the same Escherichia coli genetic background demonstrates varying importance of individual persister genes in tolerance to different antibiotics.
Ranking of persister genes in the same Escherichia coli genetic background demonstrates varying importance of individual persister genes in tolerance to different antibiotics.
复制标题
相同大肠杆菌遗传背景中的持久基因的排名表明，各个持久基因对不同抗生素的耐受性具有不同的重要性
DOI：
10.3389/fmicb.2015.01003
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发表时间：
2015
影响因子：
5.2
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Wu N;He L;Cui P;Wang W;Yuan Y;Liu S;Xu T;Zhang S;Wu J;Zhang W;Zhang Y
尽管鉴定了许多与细菌持久性现象有关的基因和途径，但这些基因在单一生物体中的相对重要性仍不清楚。在这里，使用大肠杆菌作为一个模型，我们产生了21个已知的候选持续基因的突变体，并比较这些突变体的相对重要性，在持久性的各种抗生素（氨苄青霉素，庆大霉素，诺氟沙星，甲氧苄啶）在不同的时间。我们发现oxyR、dnaK、sucB、relA、rpoS、clpB、mqsR和recA是参与对多种抗生素的持久性的突出持久性基因。这些基因映射到以下途径：抗氧化防御途径（oxyR），全局调节因子（dnaK，clpB和rpoS），能量产生（sucB），严格反应（relA），毒素-抗毒素（TA）模块（mqsR）和SOS反应（recA）。在TA模块中，排序为mqsR、lon、relE、tisAB、hipA和dinJ。有趣的是，rpoS缺失导致庆大霉素的持久性缺陷，但增加了氨苄青霉素和诺氟沙星的持久性。突变体在不同时间点对不同抗生素的持久性表现出显着差异：一些突变体（oxyR，dnaK，phoU，lon，recA，mqsR和tisAB）从早期时间点显示持久性缺陷，而其他突变体（relE，smpB，glpD，umuD和tnaA）仅在较晚的时间点显示缺陷。这些结果表明，不同的层次和重要性的持久性基因存在，持久性基因可以分为那些参与浅持久性和那些参与深持久性。我们的研究结果表明，持续现象是一个动态的过程，不同的持续基因在不同的时间发挥不同的重要作用。这些发现对于提高对持续性感染现象的理解和开发针对持续性感染者的新药以更有效地治疗持续性感染具有重要意义。
Despite the identification of many genes and pathways involved in the persistence phenomenon of bacteria, the relative importance of these genes in a single organism remains unclear. Here, using Escherichia coli as a model, we generated mutants of 21 known candidate persister genes and compared the relative importance of these mutants in persistence to various antibiotics (ampicillin, gentamicin, norfloxacin, and trimethoprim) at different times. We found that oxyR, dnaK, sucB, relA, rpoS, clpB, mqsR, and recA were prominent persister genes involved in persistence to multiple antibiotics. These genes map to the following pathways: antioxidative defense pathway (oxyR), global regulators (dnaK, clpB, and rpoS), energy production (sucB), stringent response (relA), toxin–antitoxin (TA) module (mqsR), and SOS response (recA). Among the TA modules, the ranking order was mqsR, lon, relE, tisAB, hipA, and dinJ. Intriguingly, rpoS deletion caused a defect in persistence to gentamicin but increased persistence to ampicillin and norfloxacin. Mutants demonstrated dramatic differences in persistence to different antibiotics at different time points: some mutants (oxyR, dnaK, phoU, lon, recA, mqsR, and tisAB) displayed defect in persistence from early time points, while other mutants (relE, smpB, glpD, umuD, and tnaA) showed defect only at later time points. These results indicate that varying hierarchy and importance of persister genes exist and that persister genes can be divided into those involved in shallow persistence and those involved in deep persistence. Our findings suggest that the persistence phenomenon is a dynamic process with different persister genes playing roles of variable significance at different times. These findings have implications for improved understanding of persistence phenomenon and developing new drugs targeting persisters for more effective cure of persistent infections.