title: Tailoring cytotoxicity of antimicrobial peptidomimetics with high activity against multidrug-resistant Escherichia coli.
abstract: Infections with multidrug-resistant pathogens are an increasing concern for public health. Recently, subtypes of peptide-peptoid hybrids were demonstrated to display potent activity against multidrug-resistant Gram-negative bacteria. Here, structural variation of these antibacterial peptidomimetics was investigated as a tool for optimizing cell selectivity. A protocol based on dimeric building blocks allowed for efficient synthesis of an array of peptide-peptoid oligomers representing length variation as well as different backbone designs displaying chiral or achiral peptoid residues. Lack of α-chirality in the side chains of the peptoid residues proved to be correlated to reduced cytotoxicity. Furthermore, optimization of the length of these peptidomimetics with an alternating cationic-hydrophobic design was a powerful tool to enhance the selectivity against Gram-negative pathogens over benign mammalian cells. Thus, lead compounds with a high selectivity toward killing of clinically important multidrug-resistant E. coli were identified.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Rasmus D
authors.initials: RD
authors.lastname: Jahnsen
authors.forename: Anne
authors.initials: A
authors.lastname: Sandberg-Schaal
authors.forename: Karina Juul
authors.initials: KJ
authors.lastname: Vissing
authors.forename: Hanne Mørck
authors.initials: HM
authors.lastname: Nielsen
authors.forename: Niels
authors.initials: N
authors.lastname: Frimodt-Møller
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002942:Circular Dichroism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006801:Humans; D008081:Liposomes; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D008081:Liposomes; D057786:Peptidomimetics