The development of antimicrobial a-AApeptides that suppress proinflammatory immune responses.

Herein we describe the development of a new class of antimicrobial and anti-inflammatory peptidomimetics: cyclic lipo-α-AApeptides. They have potent and broad-spectrum antibacterial activity against a range of clinically relevant pathogens, including both multidrug-resistant Gram-positive and Gram-negative bacteria. Fluorescence microscopy suggests that cyclic lipo-α-AApeptides kill bacteria by disrupting bacterial membranes, possibly through a mechanism similar to that of cationic host-defense peptides (HDPs). Furthermore, the cyclic lipo-α-AApeptide can mimic cationic host-defense peptides by antagonizing Toll-like receptor 4 (TLR4) signaling responses and suppressing proinflammatory cytokines such as tumor necrosis factor-α (TNF-α). Our results suggest that by mimicking HDPs, cyclic lipo-α-AApeptides could emerge as a new class of antibiotic agents that directly kill bacteria, as well as novel antiinflammatory agents that act through immunomodulation.