Bacteriophages versus priority pathogens: resistance mechanisms, therapeutic challenges, and opportunities for novel combinations

Antimicrobial resistance poses a critical global health threat, and renewed interest in bacteriophage (phage) therapy highlights its potential as a targeted alternative to antibiotic monotherapy. However, phage resistance in bacteria remains a key limiting factor in phage therapy, driven by evolutionary adaptations to phage exposure. Antibacterial modalities (antibiotics, adjuvants, antimicrobial peptides, and RNA-based therapeutics) could help overcome these barriers and represent untapped potential for synergistic, precision antimicrobial interventions when combined with phage therapy. Importantly, bacterial physiology and environmental context could strongly influence treatment outcomes, underscoring the need for clinically relevant models for testing combinations. Integration of multi-omics and artificial intelligence-driven approaches could help predict patterns for the development of precision therapies and support the development of novel antimicrobial interventions.