A Novel <i>Przondovirus</i> Bacteriophage Combats <i>Klebsiella pneumoniae</i> through Evolutionary Trade-off and Metabolic Reprogramming

Bacteriophages present a promising alternative to combat carbapenem-resistant hypervirulent Klebsiella pneumoniae (Kp). However, the molecular mechanisms underlying phage-host co-evolution and the action of phage-derived anti-virulence effectors remain insufficiently explored. Here, we characterized a novel Przondovirus phage, P1524, which demonstrates broad-spectrum lytic activity against high-risk clones (ST11, ST14, and ST65). Resistance to P1524 was attributed to a wcaJ missense mutation, which induced an "evolutionary trade-off" characterized by capsule loss, impaired biofilm formation, and reduced in vivo virulence. Additionally, we identified three novel phage effectors—Orf4, Orf15, and Orf23—that significantly enhanced survival in Galleria mellonella models. Mechanistically, Orf4 and Orf23 hijacked host metabolism by downregulating key enzymes (AldB_1, AlsS, and BudC), effectively blocking the 2,3-butanediol fermentation pathway. Our findings identify a novel Przondovirus phage that combats Kp through wcaJ mutation-mediated evolutionary trade-off and metabolic reprogramming via the 2,3-butanediol fermentation pathway, underscoring the potential of phage-derived metabolic inhibitors as innovative antimicrobial agents.