A capsule-dependent lytic phage for targeting multidrug-resistant and hypervirulent <i>Klebsiella pneumoniae</i>

As the threat of multidrug-resistant <i>Klebsiella pneumoniae</i> strains rises, the potential of phages as promising alternatives to antibiotics is increasingly being demonstrated. In this study, we isolated and characterized phiK2044, a highly specific and efficient lytic phage targeting the model strain <i>K. pneumoniae</i> NTUH-K2044. Demonstrating wide host compatibility, potent lytic activity, and robust environmental adaptability, phiK2044 exhibited exceptional efficacy against hypervirulent subtypes, including hypervirulent <i>K. pneumoniae</i> (45.2%), sequence type 23 (87.5%), and capsular K1 (92.3%). In the mouse model, phiK2044 effectively cleared bacteria without significant side effects, highlighting its therapeutic potential. Mechanistically, we identified <i>wcaJ</i>, a gene encoding a glycosyltransferase essential for capsular synthesis, as the critical determinant of the binding of phiK2044 to the host. Beyond its clinical utility, phiK2044 represents a model for studying phage ecology, host-microbe interactions, and capsule-dependent tropism. Collectively, phiK2044 represents a valuable tool against ST23/K1 <i>K. pneumoniae</i> infections, such as liver abscesses and bacteremia.IMPORTANCEThe rise of multidrug-resistant <i>Klebsiella pneumoniae</i> demands innovative therapies. This study identifies phiK2044, a lytic phage with high specificity and efficacy against hypervirulent subtypes. It safely clears infections in mice and reveals <i>wcaJ</i>-dependent capsule synthesis as the key host interaction mechanism. Beyond its therapeutic promise, phiK2044 serves as a critical tool for studying phage-host dynamics and capsule-mediated tropism, bridging clinical solutions and fundamental research in combating antimicrobial resistance.