Lysine N(epsilon)-trimethylation, a tool for improving the selectivity of antimicrobial peptides.
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.
Fernández-Reyes
María
M
Centro de Investigaciones Biologicas CSIC, Ramiro de Maeztu, Madrid, Spain.
Díaz
Dolores
D
de la Torre
Beatriz G
BG
Cabrales-Rico
Ania
A
Vallès-Miret
Mariona
M
Jiménez-Barbero
Jesús
J
Andreu
David
D
Rivas
Luis
L
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D007891:Leishmania / Q000187:drug effects; D008239:Lysine / Q000737:chemistry*; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D014344:Trypanocidal Agents; C435762:cecropin A(1-7)melittin(2-9); D008239:Lysine