Tailoring Cytotoxicity of Antimicrobial Peptidomimetics with High Activity against Multidrug-Resistant Escherichia coli

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• 作者：Rasmus D. Jahnsen ; Anne Sandberg-Schaal ; Karina Juul Vissing ; Hanne M酶rck Nielsen ; Niels Frimodt-M酶ller ; Henrik Franzyk
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 10, 2014
• 年：2014
• 卷：57
• 期：7
• 页码：2864-2873
• 全文大小：331K
• 年卷期：v.57,no.7(April 10, 2014)
• ISSN：1520-4804

文摘

Infections with multidrug-resistant pathogens are an increasing concern for public health. Recently, subtypes of peptide鈥損eptoid hybrids were demonstrated to display potent activity against multidrug-resistant Gram-negative bacteria. Here, structural variation of these antibacterial peptidomimetics was investigated as a tool for optimizing cell selectivity. A protocol based on dimeric building blocks allowed for efficient synthesis of an array of peptide鈥損eptoid oligomers representing length variation as well as different backbone designs displaying chiral or achiral peptoid residues. Lack of 伪-chirality in the side chains of the peptoid residues proved to be correlated to reduced cytotoxicity. Furthermore, optimization of the length of these peptidomimetics with an alternating cationic鈥揾ydrophobic design was a powerful tool to enhance the selectivity against Gram-negative pathogens over benign mammalian cells. Thus, lead compounds with a high selectivity toward killing of clinically important multidrug-resistant E. coli were identified.