A common mechanism of cellular death induced by bactericidal antibiotics
A common mechanism of cellular death induced by bactericidal antibiotics
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DOI：
10.1016/j.cell.2007.06.049
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发表时间：
2007-09-07
期刊：
影响因子：
64.5
通讯作者：
Collins, James J.
中科院分区：
文献类型：
--
作者：
Kohanski, Michael A.;Dwyer, Daniel J.;Collins, James J.
抗菌素的作用模式分类是基于药物与靶点的相互作用以及由此产生的细胞功能抑制是否对细菌致命。在这里，我们展示了三大类杀菌抗生素，无论药物与靶标相互作用如何，都会刺激革兰氏阴性和革兰氏阳性细菌产生高度有害的羟基自由基，最终导致细胞死亡。相反，我们还表明，抑菌药物不会产生羟基自由基。我们证明，杀菌抗生素诱导的羟基自由基形成机制是氧化损伤细胞死亡途径的最终产物，涉及三羧酸循环、NADH的瞬时耗竭、铁-硫簇的不稳定以及Fenton反应的刺激。我们的结果表明，所有三种主要类别的杀菌药物都可以通过靶向修复羟基自由基损伤的细菌系统来增强，包括参与触发DNA损伤反应的蛋白质，例如RecA。
Antibioticmode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e. g., RecA.