End Group Modification: Efficient Tool for Improving Activity of Antimicrobial Peptide Analogues towards Gram-Positive Bacteria

TY - JOUR

T1 - End Group Modification

T2 - Efficient Tool for Improving Activity of Antimicrobial Peptide Analogues towards Gram-Positive Bacteria

AU - Jahnsen, Rasmus O

AU - Sandberg-Schaal, Anne

AU - Frimodt-Møller, Niels

AU - Nielsen, Hanne Mørck

AU - Franzyk, Henrik

N1 - Copyright © 2015. Published by Elsevier B.V.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.ejpb.2015.01.013

DO - 10.1016/j.ejpb.2015.01.013

M3 - Journal article

C2 - 25622790

SN - 0939-6411

VL - 95

SP - 40

EP - 46

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

IS - Part A

ER -