The Development of Antimicrobial α-AApeptides that Suppress Pro-inflammatory Immune Responses

• Published in: Chembiochem : a European journal of chemical biology Vol. 15; no. 5; pp. 688 - 694
• Main Authors: Padhee, Shruti, Smith, Christina, Wu, Haifan, Li, Yaqiong, Manoj, Namitha, Qiao, Qiao, Khan, Zoya, Cao, Chuanhai, Yin, Hang, Cai, Jianfeng
• Format: Journal Article
• Language: English
• Published: 21.03.2014
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201300709

Herein we describe the development of a new class of antimicrobial and anti-infective 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 pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α). Our results suggest that by mimicking host-defense peptides (HDPs), cyclic lipo-α-AApeptides may emerge to be a new class of antibiotic agents through direct bacteria killing, as well as novel anti-infective agents through immunomodulation.