Zhang Yunhan, Lan Weiqing, Sun Xiaohong
College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; Shanghai Aquatic Products Processing and Storage Engineering Technology Research Center, Shanghai 201306, China.
Int J Biol Macromol. 2025 Sep;321(Pt 2):146159. doi: 10.1016/j.ijbiomac.2025.146159. Epub 2025 Jul 20.
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.
高毒力肺炎克雷伯菌（hvKP）被归类为ESKAPE病原体，由于其抗生素耐药性和毒力因子，对全球公共卫生构成了重大威胁。hvKP引起的感染通常与高死亡率和医疗成本相关，并且该病原体倾向于形成生物膜，这进一步使治疗复杂化。因此，迫切需要针对肺炎克雷伯菌感染的新型治疗策略。噬菌体衍生的酶，包括解聚酶和内溶素，通过特异性靶向和降解细菌细胞壁和荚膜多糖，提供了一种有前景的替代抗菌策略。然而，革兰氏阴性菌的外膜限制了内溶素的活性，并且解聚酶缺乏杀菌活性进一步限制了它们的应用。未来的发展必须克服这些障碍。在这里，我们讨论肺炎克雷伯菌的毒力因子，综述解聚酶和内溶素的结构和作用机制，并总结肺炎克雷伯菌感染预防和治疗的最新研究进展。此外，基于解聚酶和内溶素疗法针对肺炎克雷伯菌感染目前面临的挑战，我们提出了一种新颖的嵌合蛋白设计，即将β-螺旋结构域与内溶素的催化结构域结合，或采用SpyTag/SpyCatcher系统促进解聚酶和内溶素的重组。这种方法旨在增强它们的抗菌和抗生物膜活性，为开发针对肺炎克雷伯菌的新型抗菌剂提供了有前景的潜力。
