Phage and endolysin-based inhibition of Klebsiella pneumoniae: from mechanisms to combination therapies.

Klebsiella pneumoniae (K. pneumoniae) is a critical ESKAPE pathogen with rapidly escalating resistance to last-line antibiotics, for which phages and their derived endolysins have emerged as promising alternatives. Phages specifically recognize bacterial surface structures, including capsular polysaccharide (CPS) and lipopolysaccharide (LPS), with their depolymerases degrading these barriers and disrupting biofilms to attenuate virulence. In parallel, endolysins directly cleave the peptidoglycan layer to induce rapid bacterial lysis. Animal model studies confirm that both phages and endolysins effectively reduce K. pneumoniae burden and improve host survival, with efficacy markedly enhanced when combined with antibiotics or antimicrobial peptides (AMPs). Although narrow host range and potential resistance evolution remain challenges, strategies such as phage cocktails, "phage training", and combination therapies (e.g., phage-antibiotic, phage-AMP, and endolysin-antibiotic combinations) have shown broad application prospects. This review details the antibacterial actions of phages and endolysins against K. pneumoniae, including their mechanisms, anti-biofilm activity, and therapeutic potential in combination therapies.