Bactericidal oncocin derivatives with superior serum stabilities

Daniel Knappe (1) , Natalja Kabankov (1) , Ralf Hoffmann (1)

1 Leipzig University / Universität Leipzig

The proline-rich antimicrobial peptide oncocin is remarkably active in vitro against a number of important Gram-negative bacteria of concern to humans owing to their increasing resistance to antibiotics, i.e. Enterobacteriaceae (, and ) and non-fermenting species ( and ). Degradation of oncocin in mouse serum was investigated in this study. Several approaches to stabilise the main cleavage sites (C-terminal to Arg-15 and N-terminal to Arg-19) by substituting either or both arginine (Arg) residues with non-proteinogenic amino acids, i.e. α-amino-3-guanidino-propionic acid, homoarginine, nitro-arginine, -methyl-arginine, β-homoarginine, -arginine (-Arg) or ornithine (Orn), were tested. These modifications were found to increase the half-life of oncocin in full mouse serum. For oncocin with two Orn residues in positions 15 and 19, the half-life in full serum increased from 25min to 3h. An increase of >8h was observed for oncocin with two -Arg residues at these same positions. The antibacterial activities of these modified sequences were slightly better than the original oncocin sequence. Moreover, the three most stable analogues were found to be bactericidal against and were not toxic to HeLa cells or haemolytic to human erythrocytes.

Mots clés: Antimicrobial peptide; AMP; Haemolytic activity; Proline-rich peptides; Serum stability

Daniel Knappe, Natalja Kabankov, Ralf Hoffmann. Bactericidal oncocin derivatives with superior serum stabilities. International Journal of Antimicrobial Agents, 2011, 37 (2), pp.166. ⟨10.1016/j.ijantimicag.2010.10.028⟩. ⟨hal-00659901⟩