Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Department of Laboratory Medicine, Microbiology Unit, National University Hospital, Singapore 119074, Singapore.
J Med Chem. 2023 Jul 13;66(13):8498-8509. doi: 10.1021/acs.jmedchem.3c00140. Epub 2023 Jun 25.
Different stapling techniques have been used recently to address the subpar performance of antimicrobial peptides (AMPs) in clinical trials with ample focus on α-helical AMPs. In comparison, a systematic evaluation of such strategies on β-hairpin AMPs is lacking. Herein, we report the design, synthesis, and evaluation of a library of all-hydrocarbon-stapled β-hairpin AMPs with variation in key parameters intended as potent therapeutics against drug-resistant pathogens. We observed an interesting interplay between the activity, stability, and structural strength. Single-stapled peptides with a 6-carbon staple at peptide termini such as 5(c) displayed the most potent activity against colistin-resistant clinical isolates. Using imaging techniques, we observed translocation of 5(c) across bacterial membranes without causing extensive damage. Overall, we have engineered novel all-hydrocarbon-stapled β-hairpin AMPs with structural and functional proficiency that can effectively combat resistant pathogens, with findings from this study a point of reference for future interests in developing novel β-hairpin AMPs.
最近，人们采用了不同的订书钉技术来解决抗菌肽（AMPs）在临床试验中的表现不佳的问题，其中大量研究集中在α-螺旋 AMPs 上。相比之下，针对β-发夹 AMPs 的此类策略的系统评估却很少。在此，我们报告了一系列全碳订书钉β-发夹 AMP 的设计、合成和评估，这些 AMP 具有变化的关键参数，旨在作为针对耐药病原体的有效治疗方法。我们观察到活性、稳定性和结构强度之间存在有趣的相互作用。在肽末端具有 6 个碳订书钉的单订书钉肽，如 5(c)，对多粘菌素耐药的临床分离株表现出最强的活性。使用成像技术，我们观察到 5(c) 在不造成广泛损伤的情况下穿过细菌膜的易位。总的来说，我们设计了新型的全碳订书钉β-发夹 AMP，它们具有结构和功能上的优势，可以有效对抗耐药病原体，本研究的结果为未来开发新型β-发夹 AMP 提供了参考。
