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Updated: Jan 31, 2026
Isolation and Identification of Waterborne Antibiotic-Resistant Bacteria and Molecular Characterization of their Antibiotic Resistance Genes
Published on: March 3, 2023
Fluoroquinolones: action and resistance
1Public Health Research Institute, 225 Warren Street, Newark, NJ 07103, USA. drlica@phri.org
Abstract:
Fluoroquinolones trap gyrase and topoisomerase IV on DNA as ternary complexes that block the movement of replication forks and transcription complexes. Studies with resistant mutants indicate that during complex formation quinolones bind to a surface alpha-helix of the GyrA and ParC proteins. Lethal action is a distinct event that is proposed to arise from release of DNA breaks from the ternary complexes. Many bacterial pathogens are exhibiting resistance due to alterations in drug permeability, drug efflux, gyrase-protecting proteins, and target topoisomerases. When selection of resistant mutants is described in terms of fluoroquinolone concentration, a threshold (mutant prevention concentration, MPC) can be defined for restricting the development of resistance. MPC varies among fluoroquinolones and pathogens; when combined with pharmacokinetics, MPC can be used to identify compounds least likely to enrich mutant subpopulations. Use of suboptimal doses and compounds erodes the efficacy of the class as a whole because resistance to one quinolone reduces susceptibility to others and/or increases the frequency at which resistance develops. When using fluoroquinolones in combination therapy, the development of resistance may be minimized by optimizing regimens for pharmacokinetic overlap.
Insights
Fluoroquinolones inhibit bacterial growth by trapping DNA gyrase and topoisomerase IV. Understanding the mutant prevention concentration (MPC) is crucial for limiting fluoroquinolone resistance in pathogens.
Area of Science:
- Microbiology
- Molecular Biology
- Pharmacology
Background:
- Fluoroquinolones are antibiotics that target bacterial DNA gyrase and topoisomerase IV.
- These enzymes are essential for DNA replication, transcription, and repair.
- Bacterial resistance to fluoroquinolones is a growing public health concern.
Purpose of the Study:
- To elucidate the mechanism of fluoroquinolone action and resistance.
- To define the mutant prevention concentration (MPC) for fluoroquinolones.
- To identify strategies for minimizing the development of fluoroquinolone resistance.
Main Methods:
- Studies with resistant bacterial mutants.
- Analysis of fluoroquinolone-protein-DNA interactions.
- Pharmacokinetic and pharmacodynamic modeling.
Main Results:
- Fluoroquinolones form ternary complexes with DNA gyrase/topoisomerase IV, inhibiting DNA replication and transcription.
- Resistance mechanisms include altered drug permeability, efflux pumps, protective proteins, and target mutations.
- A mutant prevention concentration (MPC) threshold can be defined to restrict resistance development.
- Suboptimal dosing and cross-resistance erode fluoroquinolone efficacy.
Conclusions:
- Optimizing fluoroquinolone regimens, including combination therapy with pharmacokinetic overlap, can minimize resistance.
- Understanding MPC is vital for selecting effective fluoroquinolones and preventing resistance.
- Continued research into fluoroquinolone-DNA gyrase interactions is needed to combat resistance.
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