Department of Biosystems, KU Leuven, Leuven, Belgium.
Department of Biotechnology, Ghent University, Gent, Belgium.
Crit Rev Microbiol. 2020 Sep;46(5):548-564. doi: 10.1080/1040841X.2020.1809346. Epub 2020 Sep 4.
One of the possible solutions for the current antibiotic resistance crisis may be found in (often bacteriophage-derived) peptidoglycan hydrolases. The first clinical trials of these natural enzymes, coined here as first-generation lysins, are currently ongoing. Moving beyond natural endolysins with protein engineering established the second generation of lysins. In second-generation lysins, the focus lies on improving antibacterial and biochemical properties such as antimicrobial activity and stability, as well as expanding their activities towards Gram-negative pathogens. However, solutions to particular key challenges regarding clinical applications are only beginning to emerge in the third generation of lysins, in which protein and biochemical engineering efforts focus on improving properties relevant under clinical conditions. In addition, increasingly advanced formulation strategies are developed to increase the bioavailability, antibacterial activity, and half-life, and to reduce pro-inflammatory responses. This review focuses on third-generation and advanced formulation strategies that are developed to treat infections, ranging from topical to systemic applications. Together, these efforts may fully unlock the potential of lysin therapy and will propel it as a true antibiotic alternative or supplement.
目前解决抗生素耐药性危机的一种可能方法是寻找（通常来源于噬菌体）肽聚糖水解酶。目前正在进行这些天然酶（本文称为第一代裂解酶）的首次临床试验。通过蛋白质工程超越天然内溶素，建立了第二代裂解酶。在第二代裂解酶中，重点在于改善抗菌和生化特性，如抗菌活性和稳定性，以及扩大其对革兰氏阴性病原体的活性。然而，在第三代裂解酶中，针对临床应用的特定关键挑战的解决方案才刚刚开始出现，在第三代裂解酶中，蛋白质和生化工程的努力重点是改善与临床条件相关的特性。此外，还开发了越来越先进的配方策略来提高生物利用度、抗菌活性和半衰期，并减少促炎反应。这篇综述重点介绍了为治疗从局部到全身应用的感染而开发的第三代和先进的配方策略。这些努力可能会充分挖掘裂解酶治疗的潜力，并将其作为真正的抗生素替代品或补充物推向市场。
