Molecular Mechanisms and Precision Applications of Bacteriophages Against Multidrug-Resistant Pathogens

Abstract

The relentless rise of multidrug-resistant (MDR) pathogens, particularly the ESKAPE group, has rendered many conventional antibiotics ineffective, necessitating alternative precision therapies. Bacteriophages (phages), the most abundant and highly specific natural predators of bacteria, have re-emerged as a cornerstone of next-generation antimicrobial strategies. This review elucidates the molecular mechanisms underpinning phage therapy, from receptor-specific adsorption and genome translocation to holin–endolysin-mediated lysis and the sophisticated lysis–lysogeny decision-making process. It details bacterial counter-defenses, including restriction-modification systems and CRISPR-Cas adaptive immunity, alongside phage counter-adaptations such as anti-CRISPR (Acr) proteins and SAM-lyases. Advances in synthetic biology have enabled precision engineering of phages, including tail-fiber reprogramming for expanded host range, CRISPR-armed phages for genotype-specific killing, and fully synthetic genomes with customizable therapeutic payloads. Phage-derived enzymes endolysins for rapid peptidoglycan hydrolysis and depolymerases for biofilm matrix degradation offer enzybiotic alternatives with minimal resistance potential. Clinical evidence from 2024–2025 trials demonstrates successful personalized phage cocktails against MDR S. aureus, P. aeruginosa, K. pneumoniae, and vancomycin-resistant enterococci, often in synergy with antibiotics. Regulatory harmonization (European Pharmacopoeia Chapter 5.31, EMA reflection paper, FDA reforms) and scalable GMP manufacturing platforms now support broader implementation. As AI-driven host-range prediction and phage–microbiome engineering mature, bacteriophage therapy is poised to deliver safe, effective, genotype-specific interventions that preserve the commensal microbiota and combat the global AMR crisis.