Potent Antimicrobial Activity of Lipidated Short α,γ‐Hybrid Peptides

Abstract Herein we report the potent antimicrobial activity of α,γ‐hybrid lipopeptides composed of 1:1 alternating α‐ and γ‐amino acids. Along with their potent antimicrobial activity against various Gram‐positive and Gram‐negative bacteria, these hybrid lipopeptides were found to be less hemolytic. Studies into the mechanism of action revealed that these short cationic lipopeptides bind and disrupt the bacterial cell membrane. Time–kill kinetics analyses revealed that the potent α,γ‐hybrid lipopeptides completely inhibit bacterial growth in less than 20 minutes. Overall, the promising antimicrobial activity along with lower hemolytic activity displayed by these α,γ‐hybrid lipopeptides make them well suited for further exploration into the design of potent lipopeptide antibiotics.