Phage-quinolone synergy: mechanisms, clinical strategies, and translational prospects

The escalating global crisis of bacterial antimicrobial resistance (AMR) has significantly limited the clinical efficacy of quinolone antibiotics, while the use of phages alone suffers from inherent limitations, including a narrow host spectrum and the propensity to rapidly induce phage resistance. Consequently, combined antimicrobial therapy, defined as phage-antibiotic synergy (PAS), has emerged as a pivotal direction to address the challenges. The specific objectives of this review are to systematically dissect the bidirectional synergistic and antagonistic interactions between quinolone antibiotics and bacteriophages, define the key regulatory factors governing their combined effects, and establish an evidence-based framework to guide the standardized clinical application of quinolone-based PAS. This paper systematically reviews the mechanisms underlying the synergistic and antagonistic interactions between quinolone antibiotics and bacteriophages. The synergistic effects are manifested across multiple dimensions: bacterial morphological remodeling, activation of temperate phages, disruption of biofilm barriers, potentiation of functional proteins, dual regulation of resistance evolution, and synergy with the host immune system. In contrast, antagonistic effects are primarily triggered by high-concentration antibiotics interfering with phage proliferation, adaptive phenotypic alterations of bacteria, and imbalanced administration strategies. Simultaneously, we summarize standardized clinical optimization strategies, including sequential administration, sub-inhibitory antibiotic concentrations paired with the minimum effective multiplicity of infection (MOI) of phages, rational selection of broad-host-range and highly lytic phages, and individual regimen tailoring to match the specific infectious scenario and host immune status. We further analyze key challenges in the clinical translation of this therapeutic approach and propose future research directions, offering a framework to guide both mechanistic studies and clinical implementation of PAS as a strategy to mitigate antimicrobial resistance.