Searching for the perfect match: can non-antibiotic antimicrobials improve bacteriophage performance?

The rapid spread of multidrug-resistant (MDR) bacteria worldwide has significantly reduced the effectiveness of traditional antibiotics, leading to increased interest in bacteriophages as alternative or supplementary antimicrobial agents. While phage therapy has notable benefits, such as high specificity and minimal impact on beneficial microbiota, its use alone is limited by factors like a narrow host range, quick development of resistance, complex pharmacokinetics, and challenges in delivery within biological and environmental contexts. Although combining phages with antibiotics has been shown to improve antibacterial effects, growing regulatory restrictions and efforts to minimize antibiotic use call for the exploration of non-antibiotic combination approaches. This review explores the synergistic interactions between bacteriophages and various non-antibiotic antimicrobials, including essential oils, bacteriocins, nanoparticles, and other physicochemical or host-derived agents. We present evidence that these agents can boost phage effectiveness by altering bacterial membrane integrity, stress responses, biofilm structure, and phage stability, and by delaying the emergence of resistance. Importantly, we emphasize that the observed synergies are highly context-dependent and discuss limitations related to reproducibility, safety, and translational application. Overall, this review highlights the potential of non-antibiotic compounds as tailored adjuvants to broaden the use of phage-based antimicrobial strategies in clinical, food safety, and agricultural contexts.