Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death.-猫眼课题宝

DOI：

10.1016/j.cell.2008.09.038

发表时间：

2008-11-14

期刊：

Cell

影响因子：

64.5

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Kohanski MA;Dwyer DJ;Wierzbowski J;Cottarel G;Collins JJ

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684502/?report=classic

氨基糖苷类抗生素直接靶向核糖体，但其诱导细胞死亡的机制尚不完全清楚。最近，氧化应激被认为是杀菌抗生素杀死细菌的机制之一。在这里，我们利用系统级方法和表型分析，找出了氨基糖苷最终触发羟基自由基形成的途径。我们表明，通过禁用促进膜蛋白运输的系统，膜蛋白的误翻译和错误折叠是氨基糖苷诱导的氧化应激和细胞死亡的核心。我们还证明，通过包膜应激反应双组分系统发出的信号在这一过程中起着关键作用，并强调了氧化还原反应双组分系统的相关作用。此外，我们发现这些双组分系统在抗菌抗生素介导的氧化应激和细胞死亡中起着普遍作用，扩大了我们对抗菌抗生素诱导的常见杀伤机制的理解。

Aminoglycoside antibiotics directly target the ribosome, yet the mechanisms by which they induce cell death are not fully understood. Recently, oxidative stress has been implicated as one of the mechanisms whereby bactericidal antibiotics kill bacteria. Here we work out, using systems-level approaches and phenotypic analyses, the pathway whereby aminoglycosides ultimately trigger hydroxyl radical formation. We show, by disabling systems which facilitate membrane protein traffic, that mistranslation and misfolding of membrane proteins are central to aminoglycoside-induced oxidative stress and cell death. We also demonstrate that signaling through the envelope stress response two-component system is a key player in this process, and highlight an associated role for the redox-responsive two-component system. Additionally, we show that these two-component systems play a general role in bactericidal antibiotic-mediated oxidative stress and cell death, expanding our understanding of the common mechanism of killing induced by bactericidal antibiotics.