Hybrids of\nMembrane-Translocating Antimicrobial Peptides\nShow Enhanced Activity through Membrane Permeabilization

Antimicrobial peptides (AMPs) hold promise as useful\ntools to combat\nbacterial infection. Hybrid peptides, made by linking two independent\nAMPs together through peptide bonds, have the potential for enhancing\nantimicrobial activity. Here we explore hybrids created by combining\ntwo histone-derived antimicrobial peptides (HDAPs), BF2 and DesHDAP1,\nthat each translocate across bacterial membranes. Our work represents\nthe first systematic approach considering the activity and mechanism\nof hybrids made from two translocating AMPs. BF2/DesHDAP1 hybrids\nshowed increased antimicrobial activity against both Gram-positive\nand Gram-negative bacteria compared with the parent peptides and no\ncytotoxicity against eukaryotic cells. Introducing amino acid linkers\nbetween the parent peptides did not further enhance the antibacterial\nactivity. The increased antimicrobial activity comes from a mechanistic\nshift, as hybrid peptides show decreased translocation across bacterial\ncell membranes but increased membrane permeabilization compared to\nBF2 and DesHDAP1. These observations lay the groundwork for the further\ndesign of hybrid AMPs made from translocating peptides.