title: Enhanced membrane pore formation through high-affinity targeted antimicrobial peptides.
abstract: Many cationic antimicrobial peptides (AMPs) target the unique lipid composition of the prokaryotic cell membrane. However, the micromolar activities common for these peptides are considered weak in comparison to nisin, which follows a targeted, pore-forming mode of action. Here we show that AMPs can be modified with a high-affinity targeting module, which enables membrane permeabilization at low concentration. Magainin 2 and a truncated peptide analog were conjugated to vancomycin using click chemistry, and could be directed towards specific membrane embedded receptors both in model membrane systems and whole cells. Compared with untargeted vesicles, a gain in permeabilization efficacy of two orders of magnitude was reached with large unilamellar vesicles that included lipid II, the target of vancomycin. The truncated vancomycin-peptide conjugate showed an increased activity against vancomycin resistant Enterococci, whereas the full-length conjugate was more active against a targeted eukaryotic cell model: lipid II containing erythrocytes. This study highlights that AMPs can be made more selective and more potent against biological membranes that contain structures that can be targeted.
authors: Department of Membrane Biochemistry and Biophysics, Utrecht University, Utrecht, The Netherlands.
authors: Christopher J
authors: CJ
authors: Arnusch
authors: Roland J
authors: RJ
authors: Pieters
authors: Eefjan
authors: E
authors: Breukink
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D057930:Click Chemistry / Q000379:methods*; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D054806:Magainins / Q000737:chemistry / Q000494:pharmacology; D008563:Membrane Lipids / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D053835:Unilamellar Liposomes / Q000378:metabolism; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D023181:Antimicrobial Cationic Peptides; D054806:Magainins; D008563:Membrane Lipids; D053835:Unilamellar Liposomes; D014640:Vancomycin