Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ‐Diamino Acids

Abstract 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 GS 3 – 6 , which exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (β R ,γ S )‐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, GS 5 and GS 6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS 6K , GS 6F and GS display comparable antibacterial activity, and GS 6K and GS 6F have significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS 6K kills bacteria mainly through the disruption of the membrane.