title: Design and membrane-disruption mechanism of charge-enriched AMPs exhibiting cell selectivity, high-salt resistance, and anti-biofilm properties.
abstract: Cationic antimicrobial peptides (AMPs) are essential components of the innate immune system, offering protection against invading pathogenic bacteria. In nature, AMPs serve as antibiotics with broad-spectrum antimicrobial and anti-biofilm properties. However, low effective stability in high-salt environments and physiological instability in biological membranes limit the applicability of naturally occurring AMPs as novel therapeutics. We therefore designed short synthetic cationic peptides by substituting key residues in myxinidin, an AMP derived from the epidermal mucus of hagfish, with lysine (Lys, K), arginine (Arg, R), and tryptophan (Trp, W). The resultant myxinidin analogs exhibited strong antimicrobial activity against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains, even under high-salt conditions. Moreover, these peptides showed high binding affinity for both lipopolysaccharides and lipoteichoic acids and inhibited biofilm formation by most bacteria, but did not cause significant lysis of human red blood cells and were not cytotoxic to normal human keratinocytes. Circular dichroism analysis revealed that myxinidin and its analogs assumed α-helical or β-sheet structures within artificial liposomes and bacterial membranes. In addition, bacterial killing and membrane permeation experiments demonstrated that the myxinidin analogs permeated through bacterial membranes, leading to cytoplasmic disruption and cell death. Taken together, these findings suggest myxinidin analogs may be promising candidate antibiotic agents for therapeutic application against antibiotic-resistant bacteria.
authors.affiliation: Department of Biomedical Science, Chosun University, Gwangju, 501-759, Korea.
authors.forename: Hyo Mi
authors.initials: HM
authors.lastname: Han
authors.affiliation: Department of Biomedical Science, Chosun University, Gwangju, 501-759, Korea.
authors.forename: Ramamourthy
authors.initials: R
authors.lastname: Gopal
authors.affiliation: Department of Biomedical Science, Chosun University, Gwangju, 501-759, Korea. y_k_park@chosun.ac.kr.|Research Center for Proteineous Materials, Chosun University, Gwangju, 501-759, Korea. y_k_park@chosun.ac.kr.
authors.forename: Yoonkyung
authors.initials: Y
authors.lastname: Park
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D002942:Circular Dichroism; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects; D029941:Fish Proteins / Q000737:chemistry / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D008070:Lipopolysaccharides / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D055049:Salt Tolerance; D013329:Structure-Activity Relationship; D013682:Teichoic Acids / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D029941:Fish Proteins; D008070:Lipopolysaccharides; D009842:Oligopeptides; D013682:Teichoic Acids; C000601319:myxinidin peptide, Myxine glutinosa; C009900:lipoteichoic acid
keywords: Anti-biofilm; Antibiotic-resistant bacteria; Antimicrobial peptide; Circular dichroism