Improved Cell Selectivity of Symmetric α-Helical Peptides Derived From Trp-Rich Antimicrobial Peptides

摘要

Although Trp-rich antimicrobial peptides(TRAMPs)such as tritrpticin and indolicidin exert potent antimicrobial activity,they have several drawbacks in therapeutic application,such as low cell selectivity and strong hemolytic activity.Here,we designed α-helical TRAMPs with symmetric amino acid sequences based on pseudo-symmetric tritrpticin and indolicidin.Compared with the parental pseudo-symmetric TRAMPs,the symmetric a-helical TRAMPs were highly effective against Gram-positive bacteria,including clinically isolated methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium.The symmetric a-helical TRAMPs exhibited negligible or very low toxicity against mammalian cells,including human erythrocytes.The symmetric peptides caused a rapid collapse of bacterial membrane potential and destabilized negatively charged lipid membranes,indicating that they act on the bacterial cytoplasmic membrane as a primary mode of action.Taken together,these findings imply that symmetric TRAMPs with an a-helical structure offer significant potential for development as novel therapeutics to overcome the problem of antibiotic resistance in Gram-positive pathogens.