The development of antimicrobial α-aapeptides that suppress proinflammatory immune responses

Abstract

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. Dual functionality: We have developed a series of cyclic lipo-α-AApeptides that display potent and broad-spectrum antimicrobial activity against a range of clinically relevant bacterial pathogens. In addition, they can also harness immune responses by antagonizing Toll-like receptor signaling and suppressing proinflammatory cytokines. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.