Journal
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
Volume 95, Issue -, Pages 40-46Publisher
ELSEVIER
DOI: 10.1016/j.ejpb.2015.01.013
Keywords
Peptide analogues; Staphylococcus aureus; Enterococcus faecium; Escherichia coli; Acinetobacter baumannii; Antibacterial; Cytotoxicity; Hemolysis; Selectivity
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Funding
- Danish Council for Strategic Research [09-067075]
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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. (C) 2015 Elsevier B.V. All rights reserved.
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