Kohanski Michael A, Dwyer Daniel J, Wierzbowski Jamey, Cottarel Guillaume, Collins James J
Department of Biomedical Engineering, Center for BioDynamics, and Center for Advanced Biotechnology, Boston University, Boston, MA 02215, USA.
Cell. 2008 Nov 14;135(4):679-90. doi: 10.1016/j.cell.2008.09.038.
Aminoglycoside antibiotics, such as gentamicin and kanamycin, directly target the ribosome, yet the mechanisms by which these bactericidal drugs 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 use systems-level approaches and phenotypic analyses to provide insight into the pathway whereby aminoglycosides ultimately trigger hydroxyl radical formation. We show, by disabling systems that facilitate membrane protein traffic, that mistranslation and misfolding of membrane proteins are central to aminoglycoside-induced oxidative stress and cell death. Signaling through the envelope stress-response two-component system is found to be a key player in this process, and the redox-responsive two-component system is shown to have an associated role. 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.
氨基糖苷类抗生素，如庆大霉素和卡那霉素，直接作用于核糖体，然而这些杀菌药物诱导细胞死亡的机制尚未完全明确。最近，氧化应激被认为是杀菌抗生素杀死细菌的机制之一。在此，我们运用系统层面的方法和表型分析，以深入了解氨基糖苷类药物最终引发羟基自由基形成的途径。我们通过破坏促进膜蛋白运输的系统表明，膜蛋白的错误翻译和错误折叠是氨基糖苷类药物诱导氧化应激和细胞死亡的核心。发现通过包膜应激反应双组分系统的信号传导是这一过程中的关键因素，并且氧化还原反应双组分系统显示出相关作用。此外，我们表明这两个双组分系统在杀菌抗生素介导的氧化应激和细胞死亡中发挥普遍作用，扩展了我们对杀菌抗生素诱导杀伤的共同机制的理解。
