Abstract

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.

摘要

当前的抗生素耐药性危机的一种可能解决方案可能是（通常是噬菌体衍生的）肽聚糖水解酶。这些天然酶的第一批临床试验，即第一代溶素，目前正在进行中。通过蛋白质工程技术超越天然的内溶素建立了第二代溶素。在第二代溶素中，重点在于改善抗菌和生化特性，例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，针对临床应用的特定关键挑战的解决方案只是在第三代溶素中才开始出现，其中蛋白质和生化工程的工作重点是改善临床条件下相关的特性。此外，开发了越来越先进的制剂策略，以提高生物利用度，抗菌活性和半衰期，并减少促炎反应。这篇综述集中在第三代和先进的配方策略上，这些策略被开发用于治疗感染，从局部应用到全身应用。在一起，这些努力可能会完全释放出溶素治疗的潜力，并将推动它成为真正的抗生素替代品或补充剂。