细菌整体代谢与新抗生素及抗生素增效剂靶标  

Intact metabolism of bacteria and targets of new antibiotics and antibiotic synergism

作　　者：刘聪 冯佳妮 李玮玮 朱伟伟 薛云新[1] 王岱[1] 赵西林[1] Liu Cong;Feng Jia-ni;Li Wei-wei;Zhu Wei-wei;Xue Yun-xin;Wang Dai;Zhao Xi-lin(State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,School of Public Health,Xiamen University,Xiamen 361102)

机构地区：[1]厦门大学公共卫生学院分子疫苗学和分子诊断学国家重点实验室,厦门361102

出　　处：《中国抗生素杂志》2022年第4期313-320,共8页Chinese Journal of Antibiotics

基　　金：国家自然科学基金项目(No.81971905);福建省海洋经济发展补助资金项目(No.FJHJF-L-2019-4);2018年福建省中青年教师教育科研项目(No.JT180009)。

摘　　要：抗菌药物的滥用加速了细菌耐药的产生与传播,每年因耐药细菌导致的人口死亡和医疗成本耗费都极为惊人。针对耐药细菌的新型抗生素研制十分缓慢,自1987年以来没有一类新型抗生素上市。研究抗生素杀菌机制以开发新药或抗生素佐剂是一种应对耐药细菌的良好策略。目前普遍认同活性氧(ROS)介导细胞死亡是抗生素杀菌的共享途径,抗生素作用于靶标介导产生原发初级损伤,诱使ROS生成,ROS造成次级细胞损伤并刺激更多ROS生成,形成一种恶性循环,最终ROS累积超过细胞氧化应激极限、致使细菌死亡。细菌胞内具有用以消除氧化应激压力的专能系统,针对性抑制这些系统可能是快速杀伤细菌的一个好策略。然而,设计靶向细菌某些代谢节点的新型抗生素或相关佐剂很可能更为简单、有效,生物体代谢是一个巨大的相互协作网络,关键节点的扰动很容易引起代谢通路的剧烈波动,能引发细菌整体氧化应激状态改变的代谢节点有望成为潜在新抗生素或抗生素增效剂的靶标。The abuse of antibiotics accelerates the emergence and spread of bacterial drug resistance.The death toll caused by drug-resistant bacteria and the medical and economic cost for treatment of drug-resistant infections become increasing high year-over-year.However,the development of new antibiotics against drug-resistant bacteria is relatively slow.Since 1987,no new class of antibiotics has been brought to the market.It is a good alternative strategy to develop new drugs or antibiotic adjuvants by studying the bactericidal mechanism of antibiotics.It is now generally accepted that reactive oxygen species(ROS)-mediated cell death is a commonly shared mechanism of antibiotic lethality.Binding of antibiotics to their cellular targets produces primary lesion and initial round of ROS.ROS subsequently cause secondary damage in bacterial macromolecules and stimulate more ROS generation,leading to a vicious circle.Finally,ROS accumulation exceeds the capacity of cellular oxidative stress response to detoxify,resulting in bacterial death.There are some specific detoxification systems countering oxidative stress in bacterial cells,targeting these systems may constitute a good way to kill bacteria by lowing ROS elimination.However,since ROS are generated during cellular energetic metabolism,it may be more flexible and effective to design new antibiotics or related adjuvants by targeting some metabolic nodes of bacteria to elevate ROS production.The metabolism pathways consist a huge collaborative network.Perturbation of certain nodes in the network can easily cause the fluctuation of the overall metabolism and ROS generation.Such metabolic nodes whose perturbation can cause the change of the overall cellular oxidative stress state may serve as potential targets for new antibiotics or antibiotic potentiators.

关 键 词：抗生素杀菌 整体代谢 活性氧(ROS) 氧化应激反应 

分 类 号：R978.1[医药卫生—药品]