Lysine N^ε-Trimethylation, a Tool for Improving the Selectivity of Antimicrobial Peptides

Abstract

The effects of lysine N(epsilon)-trimethylation at selected positions of the antimicrobial cecropin A-melittin hybrid peptide KWKLFKKIGAVLKVL-amide have been studied. All five monotrimethylated, four bis-trimethylated plus the per-trimethylated analogues have been synthesized and tested for antimicrobial activity on Leishmania parasites and on Gram-positive and -negative bacteria, as well as for hemolysis of sheep erythrocytes as a measure of cytotoxicity. The impact of trimethylation on the solution conformation of selected analogues has been evaluated by NMR, which indicates a slight decrease in the alpha-helical content of the modified peptides, particularly in the N-terminal region. Trimethylation also enhances the proteolytic stability of mono- and bis-trimethylated analogues by 2-3-fold. Although it tends to lower antimicrobial activity in absolute terms, trimethylation causes an even higher decrease in hemolytic activity and therefore results in improved selectivity for several analogues. The monotrimethylated analogue at position 6 shows the overall best selectivity against both the Leishmania donovani protozoan and Acinetobacter baumannii, a Gram-negative bacterium of increasing clinical concern.

Detailed SAR and PCA of the Tyrocidines and Analogues Towards Leucocin A‐Sensitive and Leucocin A‐Resistant Listeria monocytogenes

“…monocytogenes . The known consequences of Orn trimethylation include (i) preserving the overall charge, (ii) higher bulkiness and hydrophobicity of the side chain and (iii) quaternary amino group with no hydrogen bonding ability . However, according to the reverse‐phase (C 18 ) HPLC retention times, the trimethylation of Orn 9 did not lead to an overall increased hydrophobicity, as the trimethylated analogue eluted earlier than TrcA (Table ).…”

The Acinetobacter baumannii Oxymoron: Commensal Hospital Dweller Turned Pan-Drug-Resistant Menace

“…Several methods may be used to overcome this issue although these may sometimes not be easy to apply due to a possible loss of the effectiveness of peptides upon changes in their structure. d -Amino acids, stable to proteases (Chen et al, 2006; Friedman, 2010) may be used as well as both methylation and fluorination of specific amino acids (Meng and Kumar, 2007; Fernández-Reyes et al, 2010). Another option, albeit sometimes less effective in terms of activity due to the loss of one positive charge which is important for the interaction with membranes, is cyclation (Molhoek et al, 2011).…”

1,3,5‐Triazino Peptide Derivatives: Synthesis, Characterization, and Preliminary Antileishmanial Activity

“…Furthermore, the antileishmanial effect of much more structurally complex peptides has also been reported. For example, viridamide A (Supporting Information) obtained from Oscillatoria nigroviridis showed antileishmanial activity toward L. mexicana with an IC 50 value of 1.5 μ m ; symplocamide A (Supporting Information) exhibited antileishmanial activity toward L. donovani with an IC 50 value of 9.5 μ m ; and the most active cecropin A–melittin hybrid peptide KWKLFKKIGAVLKVL‐NH 2 had an IC 50 value of 1.8 μ m (SI=26.8) against L. donovani . In comparison to these observations, some of the 1,3,5‐triazine–peptide hybrids synthesized herein showed an improvement in both antileishmanial activity and SI regarding antiamastigote activity, as exemplified by 7 a (IC 50 =1.4±0.04 μ m and SI=2457.88), whereas other derivatives, such as 7 d , 7 e , and 7 g , showed an improvement in terms of SI.…”