Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis.
Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis.
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DOI：
10.1016/j.molcel.2010.01.003
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发表时间：
2010-02-12
期刊：
影响因子：
16
通讯作者：
Collins JJ
中科院分区：
文献类型：
--
作者：
Kohanski MA;DePristo MA;Collins JJ
抗生素耐药性通过诸如对天然存在的耐药突变体的选择以及水平基因转移等机制产生。最近，氧化应激被认为是杀菌性抗生素杀死细菌的机制之一。在此我们表明，亚致死水平的杀菌性抗生素会诱导突变，导致一系列抗生素的最小抑菌浓度出现不同程度的增加，且与药物靶点无关。这种突变的增加与活性氧（ROS）的增加相关，并且可被活性氧清除剂硫脲和厌氧条件所抑制，这表明亚致死浓度的抗生素通过刺激活性氧的产生来诱导突变。我们证明这些效应可导致突变菌株对所用抗生素敏感，但对其他抗生素耐药。这项工作建立了一种基于自由基的分子机制，即亚致死水平的抗生素可导致多药耐药性，这对广泛使用和滥用抗生素具有重要影响。
Antibiotic resistance arises through mechanisms such as selection of naturally occurring resistant mutants and horizontal gene transfer. Recently, oxidative stress has been implicated as one of the mechanisms whereby bactericidal antibiotics kill bacteria. Here we show that sub-lethal levels of bactericidal antibiotics induce mutagenesis, resulting in heterogeneous increases in the minimum inhibitory concentration for a range of antibiotics, irrespective of the drug target. This increase in mutagenesis correlates with an increase in ROS, and is prevented by the ROS scavenger thiourea and by anaerobic conditions, indicating that sub-lethal concentrations of antibiotics induce mutagenesis by stimulating the production of ROS. We demonstrate that these effects can lead to mutant strains that are sensitive to the applied antibiotic but resistant to other antibiotics. This work establishes a radical-based molecular mechanism whereby sub-lethal levels of antibiotics can lead to multidrug resistance, which has important implications for the widespread use and misuse of antibiotics.
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