Biological and structural effects of the conjugation of an antimicrobial decapeptide with saturated, unsaturated, methoxylated and branched fatty acids

Abstract

The increasing bacterial resistance against conventional antibiotics has led to the search for new antimicrobial drugs with different modes of action. Cationic antimicrobial peptides (AMPs) and lipopeptides are promising candidates to treat infections because they act on bacterial membranes causing rapid destruction of sensitive bacteria. In this study, a decapeptide named A2 (IKQVKKLFKK) was conjugated at the N-terminus with saturated, unsaturated, methoxylated and methyl -branched fatty acids of different chain lengths (C8 - C20), the antimicrobial and structural properties of the lipopeptides being then investigated. The attachment of the fatty acid chain significantly improved the antimicrobial activity of A2 against bacteria, and so, endowed it with moderated antifungal activity against yeast strains belonging to genus Candida. Lipopeptides containing hydrocarbon chain lengths between C8 and C14 were the best antibacterial compounds (MIC = 0.7 to 5.8 μM), while the most active compounds against yeast were A2 conjugated with methoxylated and enoic fatty acids (11.1 to 83.3 μM). The improvement in antimicrobial activity was mainly related to the amphipathic secondary structure adopted by A2 lipopeptides in the presence of vesicles that mimic bacterial membranes. Peptide conjugation with long hydrocarbon chains (C12 or more), regardless of their structure, significantly increased toxicity towards eukaryotic cells, resulting in a loss of selectivity. These findings suggest that A2-derived lipopeptides are potential good candidates for the treatment of infectious diseases caused by bacteria and opportunistic pathogenic yeast belonging to genus Candida. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Dual-Mechanism Glycolipidpeptide with High Antimicrobial Activity, Immunomodulatory Activity, and Potential Application for Combined Antibacterial Therapy

“…The introduction of fatty acids in AMPs can improve the ability to form secondary structures or oligomerization when interacting with bacterial membrane, thereby improving the antimicrobial effect. − Herein, a series of lipopeptides (Table ) were synthesized by modifying P1 with fatty acids, which had the best activity among the four skeletons (Table ). Figure c is the line model of GLP6, and the MS spectra of AMPs are shown in Figure d and Figure S1, which indicated the AMPs were successfully synthesized.…”

Development and evaluation of cationic amphiphilic antimicrobial 2,5‐diketopiperazines

“…The pure cis enantiomer 18 did not differ in activity from the mixture 15 . These observed antifungal activities are also significantly higher than those recently reported for the cationic peptidomimetics prepared by Larsen et al and the fatty acid AMP conjugates reported by Húmpola and coworkers …”

Glycosylation and Lipidation Strategies: Approaches for Improving Antimicrobial Peptide Efficacy

“…As demonstrated by Húmpola et al, lipopeptides with longer chains of C17 and C20 were not active against bacteria and Candida species, probably due to their strong ability to self-assemble, whereas the best activity was observed for lipopeptides with fatty acids of C8 and C14 with an MIC of between 0.7 and 5.8 μM [ 89 ].…”