据一项新的研究报告,抗生素可杀灭细菌,但其长期使用可引起线粒体功能障碍并对健康的哺乳动物细胞施加氧化应激作用。这些发现可帮助解释为什么这些药物会在许多长期接受治疗的患者中引发问题。抗生素长期以来一直是对抗感染性疾病的标准武器。随着在医学和农业中的过度使用抗生素和抗生素抗药性问题变得日益紧迫,在抗生素辩论中又出现了另外一个因子——它们对健康细胞的影响。长期使用抗生素一直与各种副作用有关系,其中包括听力丧失和肾脏损害。传统思维认为抗生素通过攻击诸如细胞壁组装及蛋白质合成等标靶来杀灭细菌。然而,数项最近的研究显示,抗生素可能会引发活性氧或ROS的产生,而ROS可破坏细菌的DNA。然而,关于抗生素是否会在哺乳动物细胞中诱导ROS的产生仍然存在疑问。
Sameer Kalghatgi在这里特别观察了杀菌性或可杀死细菌的抗生素对哺乳动物细胞的影响。研究人员观察到,3种不同的杀菌性抗生素(喹诺酮类、β-内酰胺类、氨基糖苷类)全都会在实验室中的人类细胞培养中诱导ROS的产生。这种氧化应激会对健康的DNA、蛋白质及膜脂质造成伤害。文章的作者在进行更仔细的观察时发现,杀菌性抗生素会扰乱细胞线粒体的电子传递链,从而导致ROS的积聚。给予临床剂量杀菌性抗生素的小鼠会在其血液和乳腺腺体中出现类似的氧化性损害的迹象。然而,用强力抗氧化剂N-乙酰半胱氨酸进行治疗可逆转ROS的损害,而不会降低抗生素的杀菌性能。值得注意的是,文章的作者发现四环素——这是一种限制细菌生长但不会杀灭细菌的抑菌性抗生素——不会在细胞内诱发ROS的损伤。这些发现提示,来自杀菌性抗生素的细胞损伤可通过服用抗氧化剂或通过改用抑菌性抗生素而得到预防。然而,未来人们需要进行研究来证实这些药物在人体内的氧化应激作用。一则相关的《焦点》文章就这些发现进行了讨论。(生物谷Bioon.com)
生物谷推荐英文摘要:
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006055
Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells
Sameer Kalghatgi1,*, Catherine S. Spina1,2,3,*, James C. Costello1, Marc Liesa3, J. Ruben Morones-Ramirez1, Shimyn Slomovic1, Anthony Molina3,4, Orian S. Shirihai3 and James J. Collins1,2,3
Prolonged antibiotic treatment can lead to detrimental side effects in patients, including ototoxicity, nephrotoxicity, and tendinopathy, yet the mechanisms underlying the effects of antibiotics in mammalian systems remain unclear. It has been suggested that bactericidal antibiotics induce the formation of toxic reactive oxygen species (ROS) in bacteria. We show that clinically relevant doses of bactericidal antibiotics—quinolones, aminoglycosides, and β-lactams—cause mitochondrial dysfunction and ROS overproduction in mammalian cells. We demonstrate that these bactericidal antibiotic–induced effects lead to oxidative damage to DNA, proteins, and membrane lipids. Mice treated with bactericidal antibiotics exhibited elevated oxidative stress markers in the blood, oxidative tissue damage, and up-regulated expression of key genes involved in antioxidant defense mechanisms, which points to the potential physiological relevance of these antibiotic effects. The deleterious effects of bactericidal antibiotics were alleviated in cell culture and in mice by the administration of the antioxidant N-acetyl-L-cysteine or prevented by preferential use of bacteriostatic antibiotics. This work highlights the role of antibiotics in the production of oxidative tissue damage in mammalian cells and presents strategies to mitigate or prevent the resulting damage, with the goal of improving the safety of antibiotic treatment in people.