title: Analogues of the frog skin peptide alyteserin-2a with enhanced antimicrobial activities against Gram-negative bacteria.
abstract: 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, α-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 µM). Antimicrobial potency was increased further by the additional substitution Ser⁷ →Lys, but the resulting analogue remained cytotoxic to erythrocytes (LC₅₀=38 µM). 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 µM) but appreciably lower haemolytic activity (LC₅₀=185 µM) and cytotoxicity against A549 human alveolar basal epithelial cells (LC₅₀=65 µM). The analogue shows potential for treatment of nosocomial pulmonary infections caused by bacteria that have developed resistance to commonly used antibiotics.
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, 17666 Al-Ain, United Arab Emirates. jmconlon@uaeu.ac.ae
authors.forename: J Michael
authors.initials: JM
authors.lastname: Conlon
authors.forename: Milena
authors.initials: M
authors.lastname: Mechkarska
authors.forename: Kholoud
authors.initials: K
authors.lastname: Arafat
authors.forename: Samir
authors.initials: S
authors.lastname: Attoub
authors.forename: Agnes
authors.initials: A
authors.lastname: Sonnevend
mesh_terms: D000595:Amino Acid Sequence; D029845:Amphibian Proteins / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001001:Anura; D002176:Candida albicans / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006801:Humans; D007928:Lethal Dose 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D012867:Skin / Q000737:chemistry*
chemical_list: D029845:Amphibian Proteins; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; C573618:alyteserin-2a peptide, Alytes obstetricans