What mechanism does E. coli (Escherichia coli) use to produce resistance to quinolones?

Mechanisms of Quinolone Resistance in E. coli

E. coli develops resistance to quinolones through three primary mechanisms: chromosomal mutations in target enzymes (DNA gyrase and topoisomerase IV), decreased outer membrane permeability, and active efflux pumps that expel the drug from the cell.

Primary Resistance Mechanisms

Target Site Mutations (Most Important)

• Chromosomal mutations in DNA gyrase (gyrA and gyrB genes) and topoisomerase IV (parC and parE genes) are the most critical resistance mechanisms, as these are the enzymes that quinolones inhibit 1
• These target site mutations can require up to 500-fold increased quantities of fluoroquinolones to achieve the same level of DNA synthesis inhibition seen in susceptible strains 2
• Multiple mutations in these target genes lead to high-level fluoroquinolone resistance, with each additional mutation incrementally increasing the minimum inhibitory concentration 1

Decreased Membrane Permeability

• Changes in outer membrane proteins and lipopolysaccharides reduce quinolone uptake by 1.5- to 3-fold, though this mechanism alone produces only modest resistance 2
• This permeability reduction affects fluoroquinolones more than nalidixic acid, explaining why some strains remain susceptible to nalidixic acid while resistant to fluoroquinolones 2
• Outer membrane alterations typically work synergistically with target site mutations to produce clinically significant resistance levels 2

Active Efflux Pumps

• Efflux pumps actively transport quinolones out of the bacterial cell, preventing drug accumulation at therapeutic concentrations 1
• This mechanism contributes to resistance but is generally less important than target site mutations for achieving high-level resistance 1
• Efflux systems can affect multiple drug classes simultaneously, contributing to multidrug resistance patterns 1

Plasmid-Mediated Resistance

• Plasmid-encoded qnr genes represent an emerging mechanism that confers low-level quinolone resistance and can be horizontally transferred between bacteria 3
• The qnr determinant is often located on conjugative plasmids (approximately 180 kb) within class 1 integrons, frequently associated with other resistance genes including extended-spectrum beta-lactamases 3
• Plasmid-mediated resistance typically produces lower-level resistance compared to chromosomal mutations but facilitates rapid spread of resistance and may serve as a stepping stone for selection of higher-level chromosomal mutations 3

Clinical Implications

Cross-Resistance Pattern

• Because all quinolones inhibit the same target enzymes, resistance to one quinolone confers decreased susceptibility to all members of the class 1
• This cross-resistance means that switching between different quinolones (e.g., from ciprofloxacin to levofloxacin) will not overcome resistance in most cases 1

Epidemiological Concerns

• Quinolone-resistant E. coli has become common in many communities, with resistance rates exceeding 10% in multiple regions, making empirical quinolone use problematic 4
• Quinolones should not be used empirically unless local hospital surveillance indicates ≥90% susceptibility of E. coli to quinolones 4
• Previous fluoroquinolone therapy within 3 months is a major risk factor for harboring quinolone-resistant organisms 4

Resistance Selection

• The selective pressure from fluoroquinolone use drives resistance evolution, with resistance frequency increasing proportionally to fluoroquinolone consumption in both hospital and community settings 5
• Resistance development is not primarily due to clonal spread but rather independent selection events across diverse E. coli strains 5

Common Pitfalls

• Avoid assuming that nalidixic acid susceptibility predicts fluoroquinolone susceptibility—strains can exhibit peculiar resistance phenotypes where they remain nalidixic acid-susceptible while being fluoroquinolone-resistant due to specific combinations of permeability changes and target alterations 2
• Do not rely on single-step mutation selection in laboratory settings to predict clinical resistance patterns, as clinical resistance often requires multiple sequential mutations that are difficult to replicate experimentally 2
• Recognize that multidrug resistance is frequently associated with quinolone resistance, as plasmids carrying qnr genes often harbor multiple resistance determinants affecting beta-lactams, aminoglycosides, and other drug classes 3