Analogues of the frog skin peptide alyteserin-2a with enhanced antimicrobial activities against Gram-negative bacteria

The emergence of strains of multidrug-resistant Gram-negative bacteria mandates a search for new types of antimicrobial agents. Alyteserin-2a (ILGKLLSTAAGLLSNL.NH2) is a cationic, a-helical peptide, first isolated from skin secretions of the midwife toad, Alytes obstetricans, which displays relatively weak antimicrobial and haemolytic activities. Increasing the cationicity of alyteserin-2a while maintaining amphipathicity by the substitution Gly11??Lys enhanced the potency against both Gram-negative and Gram-positive bacteria by between fourfold and 16-fold but concomitantly increased cytotoxic activity against human erythrocytes by sixfold (mean concentration of peptide producing 50% cell death; LC50?=?24?mu m). Antimicrobial potency was increased further by the additional substitution Ser7?Lys, but the resulting analogue remained cytotoxic to erythrocytes (LC50?=?38?mu m). However, the peptide containing d-lysine at positions 7 and 11 showed high potency against a range of Gram-negative bacteria, including multidrug-resistant strains of Acinetobacter baumannii and Stenotrophomonas maltophilia (minimum inhibitory concentration?=?8?mu m) but appreciably lower haemolytic activity (LC50?=?185?mu m) and cytotoxicity against A549 human alveolar basal epithelial cells (LC50?=?65?mu m). The analogue shows potential for treatment of nosocomial pulmonary infections caused by bacteria that have developed resistance to commonly used antibiotics. Copyright (c) 2012 European Peptide Society and John Wiley & Sons, Ltd.