Lipo-纬-AApeptides as a New Class of Potent and Broad-Spectrum Antimicrobial Agents

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• 作者：Youhong Niu ; Shruti Padhee ; Haifan Wu ; Ge Bai ; Qiao Qiao ; Yaogang Hu ; Lacey Harrington ; Whittney N. Burda ; Lindsey N. Shaw ; Chuanhai Cao ; Jianfeng Cai
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：4003-4009
• 全文大小：334K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

There is increasing demand to develop antimicrobial peptides (AMPs) as next generation antibiotic agents, as they have the potential to circumvent emerging drug resistance against conventional antibiotic treatments. Non-natural antimicrobial peptidomimetics are an ideal example of this, as they have significant potency and in vivo stability. Here we report for the first time the design of lipidated 纬-AApeptides as antimicrobial agents. These lipo-纬-AApeptides show potent broad-spectrum activities against fungi and a series of Gram-positive and Gram-negative bacteria, including clinically relevant pathogens that are resistant to most antibiotics. We have analyzed their structure鈥揻unction relationship and antimicrobial mechanisms using membrane depolarization and fluorescent microscopy assays. Introduction of unsaturated lipid chain significantly decreases hemolytic activity and thereby increases the selectivity. Furthermore, a representative lipo-纬-AApeptide did not induce drug resistance in S. aureus, even after 17 rounds of passaging. These results suggest that the lipo-纬-AApeptides have bactericidal mechanisms analogous to those of AMPs and have strong potential as a new class of novel antibiotic therapeutics.