Structure鈥揂ctivity Relationship-based Optimization of Small Temporin-SHf Analogs with Potent Antibacterial Activity

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• 作者：Sonia Andr茅 ; Shannon K. Washington ; Emily Darby ; Marvin M. Vega ; Ari D. Filip ; Nathaniel S. Ash ; Katy A. Muzikar ; Christophe Piesse ; Thierry Foulon ; Daniel J. O鈥橪eary ; Ali Ladram
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：October 16, 2015
• 年：2015
• 卷：10
• 期：10
• 页码：2257-2266
• 全文大小：539K
• ISSN：1554-8937

文摘

Short antimicrobial peptides represent attractive compounds for the development of new antibiotic agents. Previously, we identified an ultrashort hydrophobic and phenylalanine-rich peptide, called temporin-SHf, representing the smallest natural amphibian antimicrobial peptide known to date. Here, we report on the first structure鈥揳ctivity relationship study of this peptide. A series of temporin-SHf derivatives containing insertion of a basic arginine residue as well as residues containing neutral hydrophilic (serine and 伪-hydroxymethylserine) and hydrophobic (伪-methyl phenylalanine and p-^tbutyl phenylalanine) groups were designed to improve the antimicrobial activity, and their 伪-helical structure was investigated by circular dichroism and nuclear magnetic resonance spectroscopy. Three compounds were found to display higher antimicrobial activity with the ability to disrupt (permeabilization/depolarization) the bacterial membrane while retaining the nontoxic character of the parent peptide toward rat erythrocytes and human cells (THP-1 derived macrophages and HEK-293). Antimicrobial assays were carried out to explore the influence of serum and physiological salt concentration on peptide activity. Analogs containing class="smallcaps">d-amino acid residues were also tested. Our study revealed that [p-^tBuF², R⁵]SHf is an attractive ultrashort candidate that is highly potent (bactericidal) against Gram-positive bacteria (including multidrug resistant S. aureus) and against a wider range of clinically interesting Gram-negative bacteria than temporin-SHf, and also active at physiological salt concentrations and in 30% serum.