Bacteriophage-derived depolymerases as antimicrobial synergists: A strategy to overcome resistance

Upon infection, bacteria form polysaccharides barriers, such as capsular polysaccharide (CPS), exopolysaccharide (EPS) and lipopolysaccharide (LPS). The barrier hinders antibiotic penetration and host immune clearance, exacerbating antimicrobial resistance crisis. Bacteriophages (phages), natural viruses that can specifically infect and kill bacteria, have evolved depolymerase to degrade the polysaccharides. This review evaluates the primary therapeutic value of depolymerases as synergists to existing therapies, systematically detailing their potential to enhance antibiotic efficacy, improve phage therapy, and augment host immunity. We further integrate an evolutionary perspective to analyze likely adaptive responses and potential strategies to eradicate resistance. Finally, the discussion addresses formulation challenges and future prospects for the clinical translation of depolymerase-based synergistic therapies.