Cathelicidin-derived Trp/Pro-rich antimicrobial peptides with lysine peptoid residue (Nlys): therapeutic index and plausible mode of action

✍ Scribed by Wan Long Zhu; Kyung–Soo Hahm; Song Yub Shin

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 346 KB
• Volume: 13
• Category: Article
• ISSN: 1075-2617
• DOI: 10.1002/psc.882

✦ Synopsis

Abstract

Recently, we designed a novel cell‐selective antimicrobial peptide (TPk) with intracellular mode of action from Pro → Nlys (Lys peptoid residue) substitution in a noncell‐selective cathelicidin‐derived Trp/Pro‐rich antimicrobial peptide, tritrpticin‐amide (TP; VRRFPWWWPFLRR‐NH~2~) (Biochemistry 2006; 45: 13007–13017). In this study, to elucidate the effect of Pro → Nlys substitution on therapeutic index and mode of action of other noncell‐selective cathelicidin‐derived Trp/Pro‐rich antimicrobial peptides and develop novel short antimicrobial peptides with high cell selectivity/therapeutic index, we synthesized Nlys‐substituted antimicrobial peptides, TPk, STPk and INk, in which all proline residues of TP, symmetric TP‐analogue (STP; KKFPWWWPFKK‐NH~2~) and indolicidin (IN; ILPWKWPWWPWRR‐NH~2~) were replaced by Nlys, respectively. Compared to parent Pro‐containing peptides (TP, STP and IN), Nlys substituted peptides (TPk, STPk and Ink) had 4‐ to 26‐fold higher cell selectivity/therapeutic index. Parent Pro‐containing peptides induced a significant depolarization of the cytoplasmic membrane of intact Staphylococcus aureus at their MIC, whereas Nlys‐substituted antimicrobial peptides did not cause visible membrane depolarization at their MIC. These results suggest that the antibacterial action of Nlys‐substituted peptides is probably not due to the disruption of bacterial cytoplasmic membranes but the inhibition of intracellular components. Taken together, our results showed that Pro → Nlys substitution in other noncell‐selective Trp/Pro‐rich antimicrobial peptides such as STP and IN as well as TP can improve the cell selectivity/therapeutic index and change the mode of antibacterial action from membrane‐disrupting to intracellular targeting. In conclusion, our findings suggested that Pro → Nlys substitution in noncell‐selective Trp/Pro‐rich antimicrobial peptides is a promising method to develop cell‐selective antimicrobial peptides with intracellular target mechanism. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.