TY - JOUR

T1 - Tailoring Cytotoxicity of Antimicrobial Peptidomimetics with High Activity against Multidrug-Resistant Escherichia coli

AU - Jahnsen, Rasmus D

AU - Sandberg-Schaal, Anne

AU - Vissing, Karina Juul

AU - Nielsen, Hanne Mørck

AU - Frimodt-Møller, Niels

AU - Franzyk, Henrik

PY - 2014/3/20

Y1 - 2014/3/20

N2 - 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.

AB - 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.

U2 - 10.1021/jm401335p

DO - 10.1021/jm401335p

M3 - Journal article

C2 - 24601601

VL - 57

SP - 2864

EP - 2873

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -