Tailoring Cytotoxicity of Antimicrobial Peptidomimetics with High Activity against Multidrug-Resistant Escherichia coli

Research output: Contribution to journalJournal articleResearchpeer-review

Rasmus D Jahnsen, Anne Sandberg-Schaal, Karina Juul Vissing, Hanne Mørck Nielsen, Niels Frimodt-Møller, Henrik Franzyk

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.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume57
Issue number7
Pages (from-to)2864-2873
ISSN0022-2623
DOIs
Publication statusPublished - 20 Mar 2014

ID: 104938985