title: Lysine N(epsilon)-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.
authors.affiliation: Centro de Investigaciones Biologicas CSIC, Ramiro de Maeztu, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Reyes
authors.forename: Dolores
authors.initials: D
authors.lastname: Díaz
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: de la Torre
authors.forename: Ania
authors.initials: A
authors.lastname: Cabrales-Rico
authors.forename: Mariona
authors.initials: M
authors.lastname: Vallès-Miret
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: David
authors.initials: D
authors.lastname: Andreu
authors.forename: Luis
authors.initials: L
authors.lastname: Rivas
mesh_terms: 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
chemical_list: 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