Bactericidal oncocin derivatives with superior serum stabilities

• Published in: International journal of antimicrobial agents 2011-02, Vol.37 (2), p.166-170
• Main Authors: Knappe, Daniel, Kabankov, Natalja, Hoffmann, Ralf
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii; Amino Acid Substitution; AMP; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - toxicity; antibacterial properties; antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacokinetics; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial Cationic Peptides - toxicity; Antimicrobial peptide; antimicrobial peptides; arginine; Biological and medical sciences; blood serum; Drug Stability; Enterobacter cloacae; erythrocytes; Escherichia coli; Escherichia coli - drug effects; Gram-negative bacteria; Haemolytic activity; Half-Life; HeLa Cells; Humans; Infectious Disease; Klebsiella pneumoniae; Klebsiella pneumoniae - drug effects; Medical sciences; Mice; Microbial Sensitivity Tests; ornithine; Pharmacology. Drug treatments; Proline-rich peptides; Pseudomonas aeruginosa; Serum - chemistry; Serum stability; toxicity
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2010.10.028

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 (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae) and non-fermenting species (Acinetobacter baumannii and Pseudomonas aeruginosa). 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, N-methyl-arginine, β-homoarginine, d-arginine (d-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 d-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 E. coli and were not toxic to HeLa cells or haemolytic to human erythrocytes.