Rutgers University, Newark, NJ, USA.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, South Xiang-An Road, Xiang-An District, Xiamen, Fujian Province, China.
Expert Rev Anti Infect Ther. 2021 May;19(5):601-618. doi: 10.1080/14787210.2021.1840353. Epub 2020 Nov 16.
Lethal stressors, including antimicrobials, kill bacteria in part through a metabolic response proposed to involve reactive oxygen species (ROS). The quinolone anti-bacterials have served as key experimental tools in developing this idea.
Bacteriostatic and bactericidal action of quinolones are distinguished, with emphasis on the contribution of chromosome fragmentation and ROS accumulation to bacterial death. Action of non-quinolone antibacterials and non-antimicrobial stressors is described to provide a general framework for understanding stress-mediated, bacterial death.
Quinolones trap topoisomerases on DNA in reversible complexes that block DNA replication and bacterial growth. At elevated drug concentrations, DNA ends are released from topoisomerase-mediated constraint, leading to the idea that death arises from chromosome fragmentation. However, DNA ends also stimulate repair, which is energetically expensive. An incompletely understood metabolic shift occurs, and ROS accumulate. Even after quinolone removal, ROS continue to amplify, generating secondary and tertiary damage that overwhelms repair and causes death. Repair may also contribute to death directly via DNA breaks arising from incomplete base-excision repair of ROS-oxidized nucleotides. Remarkably, perturbations that interfere with ROS accumulation confer tolerance to many diverse lethal agents.
致死应激源，包括抗生素，通过一种被认为涉及活性氧（ROS）的代谢反应部分杀死细菌。喹诺酮类抗生素已成为发展这一观点的关键实验工具。
区分了喹诺酮类的抑菌和杀菌作用，重点介绍了染色体片段化和 ROS 积累对细菌死亡的贡献。描述了非喹诺酮类抗生素和非抗菌应激源的作用，为理解应激介导的细菌死亡提供了一个通用框架。
喹诺酮类药物将拓扑异构酶可逆地捕获在 DNA 上，从而阻止 DNA 复制和细菌生长。在升高的药物浓度下，DNA 末端从拓扑异构酶介导的约束中释放出来，导致死亡源于染色体片段化的想法。然而，DNA 末端也会刺激修复，这是能量密集的。发生了一个尚未完全理解的代谢转变，ROS 积累。即使在喹诺酮类药物去除后，ROS 仍会继续扩增，产生二次和三次损伤，从而超过修复并导致死亡。修复也可能通过 ROS 氧化核苷酸的碱基切除修复不完全导致的 DNA 断裂直接导致死亡。值得注意的是，干扰 ROS 积累的干扰会赋予对许多不同致死剂的耐受性。
