Cheetham Max J, Huo Yunlong, Stroyakovski Maria, Cheng Li, Wan Daniel, Dell Anne, Santini Joanne M
Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, WC1E 6AA, U.K.
Department of Life Sciences, Imperial College London, London, SW7 2AZ, U.K.
Essays Biochem. 2024 Dec 17;68(5):661-677. doi: 10.1042/EBC20240015.
Klebsiella pneumoniae is an opportunistic pathogen with significant clinical relevance. K. pneumoniae-targeting bacteriophages encode specific polysaccharide depolymerases with the ability to selectively degrade the highly varied protective capsules, allowing for access to the bacterial cell wall. Bacteriophage depolymerases have been proposed as novel antimicrobials to combat the rise of multidrug-resistant K. pneumoniae strains. These enzymes display extraordinary diversity, and are key determinants of phage host range, however with limited data available our current knowledge of their mechanisms and ability to predict their efficacy is limited. Insight into the resolved structures of Klebsiella-specific capsule depolymerases reveals varied catalytic mechanisms, with the intra-chain cleavage mechanism providing opportunities for recombinant protein engineering. A detailed comparison of the 58 characterised depolymerases hints at structural and mechanistic patterns, such as the conservation of key domains for substrate recognition and phage tethering, as well as diversity within groups of depolymerases that target the same substrate. Another way to understand depolymerase specificity is by analyzing the targeted capsule structures, as these may share similarities recognizable by bacteriophage depolymerases, leading to broader substrate specificities. Although we have only begun to explore the complexity of Klebsiella capsule depolymerases, further research is essential to thoroughly characterise these enzymes. This will be crucial for understanding their mechanisms, predicting their efficacy, and engineering optimized enzymes for therapeutic applications.
肺炎克雷伯菌是一种具有重要临床意义的机会致病菌。靶向肺炎克雷伯菌的噬菌体编码特定的多糖解聚酶，这些酶能够选择性地降解高度多样的保护性荚膜，从而得以接触细菌细胞壁。噬菌体解聚酶已被提议作为新型抗菌剂，以对抗多重耐药肺炎克雷伯菌菌株的增加。这些酶表现出非凡的多样性，是噬菌体宿主范围的关键决定因素，然而，由于可用数据有限，我们目前对其作用机制和预测其疗效能力的了解也很有限。对已解析的肺炎克雷伯菌特异性荚膜解聚酶结构的深入研究揭示了不同的催化机制，链内切割机制为重组蛋白工程提供了机会。对58种已表征的解聚酶进行详细比较，提示了结构和机制模式，例如用于底物识别和噬菌体连接的关键结构域的保守性，以及靶向相同底物的解聚酶组内的多样性。另一种理解解聚酶特异性的方法是分析靶向的荚膜结构，因为这些结构可能具有噬菌体解聚酶可识别的相似性，从而导致更广泛的底物特异性。尽管我们才刚刚开始探索肺炎克雷伯菌荚膜解聚酶的复杂性，但进一步的研究对于全面表征这些酶至关重要。这对于理解它们的作用机制、预测它们的疗效以及设计用于治疗应用的优化酶将至关重要。
