Bacterial death from treatment with fluoroquinolones and other lethal stressors

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.

KEYWORDS:

• Fluoroquinolones
• reactive oxygen species
• antibiotics
• lethal stress
• bacterial death

Article highlights

• The availability of quinolone derivatives having distinct properties has facilitated dissection of lethal processes and distinguished those processes from bacteriostatic events.

• Bacterial self-destruction, mediated by self-amplifying reactive oxygen species (ROS), is a likely component of stress-mediated lethality.

• The relative contribution of ROS and primary lesions to cell death is determined by the robustness of repair and experimental conditions.

• Antimicrobial tolerance, which is mechanistically distinct from resistance, derives from interference in ROS-mediated death; surveillance for tolerance is needed to raise awareness of this potentially important contributor to antibiotic resistance.

• Challenges to the ROS-lethality hypothesis have been addressed.

Acknowledgments

We thank the following for critical comments on the manuscript: Arnold Bendich, James Berger, Tim Blower, Yuzhi Hong, George Miklos, Bo Shopsin, and Jason Yang. We also thank Yuzhi Hong for preparing the figures.

Declaration of interest

Bayer AG, Bristol-Myers-Squibb, Mylan Pharmaceuticals previously provided research support and consulting fees for both K Drlica and X Zhao. The National Institutes of Health previously provided research support, and Foamix Pharmaceuticals Inc previously provided consulting fees for both authors. Fitzpatrick, Cella, Harper & Scinto previously provided consulting fees for K Drlica. Williams & Connolly, Kirkland & Ellis and Stinson Leonard Street previously provided consulting fees for K Drlica. Bill & Melinda Gates Foundation previously provided research support and Sterne, Kessler, Goldstein & Fox P. L.L.C previously provided consulting fees for X Zhao. X Zhao also owns stock in Bristol-Myers-Squibb The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors’ work has been supported by grants from the National Institutes of Health and from the China National Natural Science Foundation.