Navigating fluoroquinolone resistance in Gram-negative bacteria: a comprehensive evaluation
Linda Kherroubi1, Joanna Bacon2, Khondaker Miraz Rahman1
1School of Cancer and Pharmaceutical Science, King's College London, London SE1 9NH, UK.
Abstract:
Since the introduction of quinolone and fluoroquinolone antibiotics to treat bacterial infections in the 1960s, there has been a pronounced increase in the number of bacterial species that have developed resistance to fluoroquinolone treatment. In 2017, the World Health Organization established a priority list of the most critical Gram-negative resistant pathogens. These included Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. In the last three decades, investigations into the mechanisms of fluoroquinolone resistance have revealed that mutations in the target enzymes of fluoroquinolones, DNA gyrase or topoisomerase IV, are the most prevalent mechanism conferring high levels of resistance. Alterations to porins and efflux pumps that facilitate fluoroquinolone permeation and extrusion across the bacterial cell membrane also contribute to the development of resistance. However, there is a growing observation of novel mutants with newer generations of fluoroquinolones, highlighting the need for novel treatments. Currently, steady progress has been made in the development of novel antimicrobial agents that target DNA gyrase or topoisomerase IV through different avenues than current fluoroquinolones to prevent target-mediated resistance. Therefore, an updated review of the current understanding of fluoroquinolone resistance within the literature is imperative to aid in future investigations.
Insights
Fluoroquinolone antibiotics face increasing bacterial resistance, driven by target enzyme mutations and altered cell membranes. Novel treatments targeting DNA gyrase and topoisomerase IV are crucial to combat resistant Gram-negative pathogens.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- The rise of bacterial resistance to quinolone and fluoroquinolone antibiotics since the 1960s poses a significant global health threat.
- The World Health Organization identified critical Gram-negative pathogens like *Klebsiella pneumoniae*, *Acinetobacter baumannii*, *Pseudomonas aeruginosa*, and *Escherichia coli* due to widespread resistance.
Purpose of the Study:
- To review the current understanding of fluoroquinolone resistance mechanisms.
- To highlight the emergence of novel fluoroquinolone-resistant mutants.
- To emphasize the need for developing novel antimicrobial agents and treatments.
Main Methods:
- Literature review of studies investigating fluoroquinolone resistance mechanisms.
- Analysis of genetic mutations in target enzymes (DNA gyrase, topoisomerase IV).
- Examination of the role of porins and efflux pumps in resistance.
Main Results:
- Mutations in DNA gyrase and topoisomerase IV are the primary mechanisms conferring high-level fluoroquinolone resistance.
- Alterations in porins and efflux pumps also contribute significantly to resistance.
- Emergence of novel resistant mutants necessitates the development of new therapeutic strategies.
Conclusions:
- Understanding fluoroquinolone resistance mechanisms is critical for developing effective treatments.
- Novel antimicrobial agents targeting DNA gyrase/topoisomerase IV via alternative pathways are under development.
- Continued research is imperative to combat the growing challenge of antibiotic resistance.
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