Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical application due to undesired hemolytic activity. With the aim of obtaining nontoxic GS analogues, we describe herein a molecular approach in which the native GS β‐turn region is replaced by synthetic β,γ‐diamino acids (β,γ‐DiAAs). Four β,γ‐DiAA diastereomers were employed to mimic the β‐turn structure to afford GS analogues GS3 –6 , which exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (βR ,γS )‐DiAA is the most‐stable β‐turn mimic. To further improve the therapeutic index (e. g., high antibacterial activity and low hemolytic activity) and to extend the molecular diversity, GS5 and GS6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS6K , GS6F and GS display comparable antibacterial activity, and GS6K and GS6F have significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS6K kills bacteria mainly through the disruption of the membrane.

中文翻译：

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带有塑料β，γ-二氨基酸的葛兰素治疗类似物的开发。

Gramicidin S（GS）是研究最广泛的抗菌肽（AMP）之一，以其强大的抗菌活性而闻名。然而，由于不希望的溶血活性，它仅限于局部应用。为了获得无毒的GS类似物，我们在本文中描述了一种分子方法，其中天然GSβ-turn区被合成的β，γ-二氨基酸（β，γ-DiAAs）取代。四个β，γ-DiAA非对映体采用模仿β转角结构，得到GS类似物GS 3 - 6，其显示出降低的溶血活性。的比较结构研究表明，（β - [R，γ小号）-DiAA是最稳定的β-turn模拟物。为了进一步改善治疗指数（例如，高抗菌活性和低溶血活性）并扩展分子多样性，GS 5和GS 6被用作结构支架以引入另外的疏水或亲水基团。我们表明，GS 6K，GS 6F和GS显示了相当的抗菌活性，并且GS 6K和GS 6F的毒性明显降低。此外，抗菌机制研究表明，GS 6K主要通过破坏膜来杀死细菌。