ReviewFrontiers in pharmacology2026
Efflux pump overexpression in fluoroquinolone multidrug resistance: molecular mechanisms, PK/PD implications, global epidemiology, and translational strategies.
Review in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Fluoroquinolones are a cornerstone of human antibacterial chemotherapy because they combine broad-spectrum bactericidal activity, high oral bioavailability, and excellent tissue penetration. However, their clinical utility is being eroded by the global spread of multidrug-resistant (MDR) pathogens. While quinolone resistance-determining region (QRDR) mutations in DNA gyrase and topoisomerase IV remain the primary determinants of high-level resistance, mounting evidence implicates active efflux pump overexpression as an important exposure-modifying mechanism. This mechanism can amplify multidrug resistance. This review provides a pharmacology-centered synthesis of fluoroquinolone mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) indices, and the mutant selection window (MSW) framework, and integrates these concepts with the structural and regulatory biology of efflux systems in major human ESKAPE pathogens. We highlight how resistance-nodulation-division (RND) pumps in Gram-negative bacteria (e.g., AcrAB-TolC, Mex-family systems) and major facilitator superfamily (MFS) pumps in Gram-positive cocci (e.g., NorA/NorB/NorC) lower intracellular drug exposure, widen the MSW, and promote stepwise acquisition of QRDR mutations and plasmid-mediated quinolone resistance. Using recent WHO GLASS data and health-economic analyses, we summarize global resistance trends and discuss the broader healthcare and macroeconomic burden associated with MDR bacterial infections. Finally, we discuss translational strategies to mitigate efflux-mediated resistance, including the preclinical pipeline of efflux pump inhibitors (EPIs), PK/PD-informed high-exposure dosing regimens, and One Health-aligned antimicrobial stewardship interventions. By linking molecular mechanism, PK/PD, epidemiology, and health economics, this review aims to inform rational dosing, drug development, and policy decisions needed to preserve the efficacy of this vital antimicrobial class.
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