Design of Right-Handed D-Sulfonyl-γ-AApeptides with Broad-Spectrum Antimicrobial Activity

Antimicrobial resistance (AMR) has severely compromised the efficacy of conventional antibiotics, posing a major threat to global public health. Antimicrobial peptides (AMPs) emerged as a potential solution to combat multidrug-resistant pathogens. However, the clinical applications of AMPs are hindered by their instability, cytotoxicity, and nonspecificity. Herein, we report a series of sulfonyl-γ-AApeptides helical foldamers, which exhibit broad-spectrum antibacterial activity and a high selectivity index against a panel of Gram-positive and -negative strains, including drug-resistant ones. The lead AApeptide AM10 demonstrated potent activity with rapid bactericidal kinetics, strong antibiofilm effects, minimal resistance development, and exceptional stability. Mechanistic studies revealed that AM10 exerts its effect through membrane perturbation and excessive reactive oxygen species (ROS) accumulation. Additionally, AM10 significantly reduced bacterial burden in a mice MRSA infection model, highlighting the sulfonyl-γ-AApeptide foldamers as a promising platform for the development of next-generation antimicrobial peptidomimetics.