The clinical application of most natural antimicrobial peptides (AMPs) is hindered by their lack of a synergistic combination of high antibacterial efficacy, low toxicity, and stability, necessitating frequent complex modifications that incur significant labor and economic costs. Therefore, it is imperative to optimize the antibacterial properties of AMPs using some simplified approach. In this study, we designed a library of β-hairpin AMPs with identical β-turn sequences (-D-Pro-Gly-) and varying repetition units (IR, FR, and WK). Ultimately, candidate peptide G(RF)3 exhibited high antibacterial activity and low toxicity; however, its stability was compromised. Moreover, we synthesized the new analogue D-G(RF)3 by D-type amino acid substitution of G(RF)3, and D-G(RF)3 demonstrated concurrent high antibacterial activity, low toxicity, and remarkable stability. Interestingly, both G(RF)3 and D-G(RF)3 exerted bactericidal effects by disrupting the bacterial membrane. However, D-G(RF)3 displayed superior antibiofilm activity with a faster bactericidal rate compared to G(RF)3 and also showed enhanced synergy with antibiotics. Furthermore, D-G(RF)3 exhibited potent in vivo bactericidal activity without inducing drug resistance and has the potential to be a novel antibiotic alternative or adjuvant.

中文翻译：

---

新型 β 发夹抗菌肽 D-G（RF）3 表现出卓越的抗菌功效


大多数天然抗菌肽 （AMPs） 的临床应用受到缺乏高抗菌功效、低毒性和稳定性的协同组合的阻碍，需要频繁的复杂修饰，从而产生巨大的劳动力和经济成本。因此，必须使用一些简化的方法优化 AMPs 的抗菌性能。在这项研究中，我们设计了一个具有相同 β 转序列 （-D-Pro-Gly-） 和不同重复单元 （IR、FR 和 WK） 的 β 发夹 AMP 库。最终，候选肽 G（RF）3 表现出高抗菌活性和低毒性;然而，它的稳定性受到了损害。此外，我们通过 G（RF）3 的 D 型氨基酸取代合成了新的类似物 D-G（RF）3，D-G（RF）3 表现出同时的高抗菌活性、低毒性和显着的稳定性。有趣的是，G（RF）3 和 D-G（RF）3 都通过破坏细菌膜来发挥杀菌作用。然而，与 G（RF）3 相比，D-G（RF）3 显示出卓越的抗生物膜活性和更快的杀菌率，并且还显示出与抗生素的增强协同作用。此外，D-G（RF）3 在不诱导耐药性的情况下表现出有效的体内杀菌活性，并有可能成为一种新型抗生素替代品或佐剂。