Phage-encoded depolymerases and endolysins as prospective strategies to combat multidrug-resistant Klebsiella pneumoniae.

Hypervirulent Klebsiella pneumoniae (hvKP), classified as ESKAPE pathogens, represent substantial global public health threats owing to their antibiotic resistance and virulence factors. Infections caused by hvKP are often associated with high mortality rates and healthcare costs, and the pathogen tends to form biofilms, which further complicates treatment. Thus, novel therapeutic strategies are urgently needed for K. pneumoniae infections. Bacteriophage-derived enzymes, including depolymerases and endolysins, provide a promising alternative antimicrobial strategy by specifically targeting and degrading bacterial cell walls and capsular polysaccharides. However, the outer membrane of Gram-negative bacteria limits the activity of endolysins, and the lack of bactericidal activity in depolymerases further restricts their application. Future development must address these obstacles. Here, we discuss the virulence factors of K. pneumoniae, review the structure and mechanisms of depolymerases and endolysins, and summarize recent research advances in the prevention and treatment of K. pneumoniae infections. Furthermore, based on the current challenges faced by depolymerase and endolysin therapies against K. pneumoniae infections, we propose a novel chimeric protein design that combines the β-helix domain with the catalytic domain of endolysin, or employs the SpyTag/SpyCatcher system to facilitate the recombination of depolymerase and endolysin. This approach aims to enhance their antibacterial and antibiofilm activities, offering promising potential for the development of new antimicrobial agents against K. pneumoniae.