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Bacterial death from treatment with fluoroquinolones and other lethal stressors
Karl Drlica1, Xilin Zhao1,2
1Rutgers University, Newark, NJ, USA.
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.
Insights
Bacterial death from antimicrobials involves reactive oxygen species (ROS). Quinolones induce ROS accumulation and DNA damage, leading to cell death even after drug removal, highlighting ROS as a key factor in bacterial demise.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Lethal stressors, including antimicrobials, induce bacterial death partly via reactive oxygen species (ROS).
- Quinolone antibacterials are crucial tools for studying ROS-mediated bacterial death.
- Bacterial responses to stressors involve complex metabolic shifts and DNA damage.
Purpose of the Study:
- To elucidate the mechanisms of quinolone-induced bacterial death, focusing on ROS accumulation and DNA fragmentation.
- To differentiate between bacteriostatic and bactericidal actions of quinolones.
- To provide a general framework for understanding stress-mediated bacterial death.
Main Methods:
- Investigating the role of topoisomerase-DNA complexes in quinolone action.
- Analyzing ROS accumulation and its amplification post-drug exposure.
- Examining DNA fragmentation and repair mechanisms in response to quinolone treatment.
Main Results:
- Quinolones trap topoisomerases on DNA, inhibiting replication and causing fragmentation at high concentrations.
- ROS accumulate significantly, even after quinolone removal, leading to amplified secondary and tertiary damage.
- DNA repair processes, including base-excision repair, can paradoxically contribute to cell death via DNA breaks.
Conclusions:
- Bacterial death induced by quinolones is strongly linked to ROS accumulation and subsequent DNA damage.
- Interfering with ROS accumulation can confer tolerance to various lethal stressors.
- Understanding these pathways is critical for developing new antimicrobial strategies.
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