Reprogramming resistance: phage-antibiotic synergy targets efflux systems in ESKAPEE pathogens

ABSTRACT Multidrug-resistant (MDR) and extensively drug-resistant (XDR) ESKAPE pathogens pose a significant global health threat due to their ability to evade antibiotics through intrinsic and acquired mechanisms. These bacteria, including Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , Escherichia coli, and Enterobacter species, evade antibiotics through intrinsic and adaptive mechanisms. Common strategies include capsule formation, biofilm, β-lactamase production, and efflux activity. Using these mechanisms, bacteria can evade the effects of antibiotics, leading to persistent and difficult-to-treat infections. Understanding the mechanisms of resistance is crucial in developing effective strategies to combat MDR and XDR ESKAPEE pathogens. A promising approach is the development of alternative treatments targeting specific resistance mechanisms in these pathogens. Bacteriophages (phages), which co-evolve with bacterial hosts, offer a dynamic therapeutic alternative by targeting pathogenic bacteria using precision-based strategies. This targeted approach can overcome antibiotic resistance and reduce the risk of damaging the beneficial microbiota. Phages can restore susceptibility in previously untreatable infections by enhancing antibiotic uptake and imposing fitness costs on resistant strains. However, therapeutic deployment faces challenges such as rapid evolution of phage resistance, inconsistent production standards, and limited regulatory pathways. This review examines the mechanistic insights into phage-antibiotic synergy, with a focus on efflux pump-mediated resistance. It discusses emerging therapeutic strategies, current clinical applications, and the translational frameworks needed to integrate phage therapy into mainstream medicine and transform the clinical management of drug-resistant ESKAPEE infections.