title: Boosting antimicrobial peptides by hydrophobic oligopeptide end tags.
abstract: A novel approach for boosting antimicrobial peptides through end tagging with hydrophobic oligopeptide stretches is demonstrated. Focusing on two peptides derived from kininogen, GKHKNKGKKNGKHNGWK (GKH17) and HKHGHGHGKHKNKGKKN (HKH17), tagging resulted in enhanced killing of Gram-positive Staphylococcus aureus, Gram-negative Escherichia coli, and fungal Candida albicans. Microbicidal potency increased with tag length, also in plasma, and was larger for Trp and Phe stretches than for aliphatic ones. The enhanced microbicidal effects correlated to a higher degree of bacterial wall rupture. Analogously, tagging promoted peptide binding to model phospholipid membranes and liposome rupture, particularly for anionic and cholesterol-void membranes. Tagged peptides displayed low toxicity, particularly in the presence of serum, and resisted degradation by human leukocyte elastase and by staphylococcal aureolysin and V8 proteinase. The biological relevance of these findings was demonstrated ex vivo and in vivo in porcine S. aureus skin infection models. The generality of end tagging for facile boosting of antimicrobial peptides without the need for post-synthesis modification was also demonstrated.
authors.affiliation: Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
authors.forename: Mukesh
authors.initials: M
authors.lastname: Pasupuleti
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Mina
authors.initials: M
authors.lastname: Davoudi
authors.forename: Jan
authors.initials: J
authors.lastname: Alenfall
authors.forename: Anna
authors.initials: A
authors.lastname: Chalupka
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002942:Circular Dichroism; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007704:Kininogens / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013552:Swine
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D007704:Kininogens; D009842:Oligopeptides; D007770:L-Lactate Dehydrogenase; D012697:Serine Endopeptidases; D019272:Leukocyte Elastase; D008666:Metalloendopeptidases; C115504:aureolysin