Antimicrobial Properties of Brevinin-2-Related Peptide and its Analogs: Efficacy Against Multidrug-Resistant Acinetobacter baumannii

Brevinin-2 related peptide (B2RP; GIWDTIKSMG10KVFAGKILQN20L.NH(2)), first isolated from skin secretions of the mink frog Lithobates septentrionalis, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by moderate hemolytic activity. The peptide adopts an alpha-helical conformation in a membrane-mimetic solvent but amphipathicity is low. Increasing amphipathicity together with hydrophobicity by the substitutions Lys16 -> Leu and Lys16 -> Ala increased hemolytic activity approximately fivefold without increasing antimicrobial potency. The substitution Leu18 -> Lys increased both cationicity and amphipathicity but produced decreases in both antimicrobial potency and hemolytic activity. In contrast, increasing cationicity of B2RP without changing amphipathicity by the substitution Asp4 -> Lys resulted in a fourfold increase in potency against Escherichia coli [minimal inhibitory concentration (MIC) = 6 mu m) and twofold increases in potency against Staphylococcus aureus (MIC = 12.5 mu m) and Candida albicans (MIC = 6 mu m) without changing significantly hemolytic activity against human erythrocytes (LC(50) = 95 mu m). The emergence of antibiotic-resistant strains of the Gram-negative bacterium Acinetobacter baumannii constitutes a serious risk to public health. B2RP (MIC = 3-6 mu m) and [Lys4]B2RP (MIC = 1.5-3 mu m) potently inhibited the growth of nosocomial isolates of multidrug-resistant Acinetobacter baumannii. Although the analogs [Lys4, Lys18]B2RP and [Lys4, Ala16, Lys18]B2RP showed reduced potency against Staphylococcus aureus, they retained activity against Acinetobacter baumannii (MIC = 3-6 mu m) and had very low hemolytic activity (LC(50) > 200 mu m).