ABSTRACT

Introduction

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.

Areas covered

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.

Expert opinion

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.

中文翻译：

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氟喹诺酮类药物和其他致死应激源治疗导致的细菌死亡

摘要

介绍

致命的压力源，包括抗菌剂，部分通过涉及活性氧 (ROS) 的代谢反应杀死细菌。喹诺酮类抗菌药物已成为发展这一想法的关键实验工具。

覆盖区域

喹诺酮类的抑菌和杀菌作用是有区别的，重点是染色体断裂和活性氧积累对细菌死亡的贡献。描述了非喹诺酮类抗菌药物和非抗菌应激物的作用，为理解压力介导的细菌死亡提供了一个总体框架。

专家意见

喹诺酮类以可逆复合物形式在 DNA 上捕获拓扑异构酶，从而阻止 DNA 复制和细菌生长。在药物浓度升高时，DNA 末端从拓扑异构酶介导的约束中释放出来，导致死亡是由染色体断裂引起的。然而，DNA 末端也会刺激修复，这在能量上是昂贵的。发生了不完全理解的代谢转变，并且 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，从而压倒修复并导致死亡。修复也可能通过由 ROS 氧化核苷酸的不完全碱基切除修复引起的 DNA 断裂直接导致死亡。值得注意的是，干扰 ROS 积累的扰动赋予对许多不同致死剂的耐受性。