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 α‐helical TRAMPs were highly effective against Gram‐positive bacteria, including clinically isolated methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus faecium. The symmetric α‐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 α‐helical structure offer significant potential for development as novel therapeutics to overcome the problem of antibiotic resistance in Gram‐positive pathogens.