title: End group modification: Efficient tool for improving activity of antimicrobial peptide analogues towards Gram-positive bacteria.
abstract: Increased incidence of infections with multidrug-resistant bacterial strains warrants an intensive search for novel potential antimicrobial agents. Here, an antimicrobial peptide analogue with a cationic/hydrophobic alternating design displaying only moderate activity against Gram-positive pathogens was optimized. Generally, introduction of hydrophobic moieties at the N-terminus resulted in analogues with remarkably increased activity against multidrug-resistant Staphylococcus aureus and Enterococcus faecium. Interestingly, the potency against Escherichia coli strains was unaffected, whereas modification with hydrophobic moieties led to increased activity towards the Gram-negative Acinetobacter baumannii. Despite increased cytotoxicity against murine fibroblasts and human umbilical vein endothelial cells, the optimized peptide analogues exhibited significantly improved cell selectivity. Overall, the most favorable hydrophobic activity-inducing moieties were found to be cyclohexylacetyl and pentafluorophenylacetyl groups, while the presence of a short PEG-like chain had no significant effect on activity. Introduction of cationic moieties conferred no effect or merely a moderate activity-promoting effect to the analogues.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: rj@sund.ku.dk.
authors.forename: Rasmus O
authors.initials: RO
authors.lastname: Jahnsen
authors.affiliation: Department of Clinical Microbiology, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Sandberg-Schaal
authors.affiliation: Department of Clinical Microbiology, Copenhagen University Hospital, Hvidovre, Denmark. Electronic address: Niels.Frimodt-Moeller@regionh.dk.
authors.forename: Niels
authors.initials: N
authors.lastname: Frimodt-Møller
authors.affiliation: Dept. Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: hanne.morck@sund.ku.dk.
authors.forename: Hanne Mørck
authors.initials: HM
authors.lastname: Nielsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: henrik.franzyk@sund.ku.dk.
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004912:Erythrocytes / Q000187:drug effects / Q000382:microbiology / Q000502:physiology; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000379:methods; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D010446:Peptide Fragments
keywords: Acinetobacter baumannii; Antibacterial; Cytotoxicity; Enterococcus faecium; Escherichia coli; Hemolysis; Peptide analogues; Selectivity; Staphylococcus aureus