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

J. Michael Conlon, Milena Mechkarska, Kholoud Arafat, Samir Attoub, Agnes Sonnevend

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

The emergence of strains of multidrug-resistant Gram-negative bacteria mandates a search for new types of antimicrobial agents. Alyteserin-2a (ILGKLLSTAAGLLSNL.NH 2) 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 Gly 11→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; LC 50=24μm). Antimicrobial potency was increased further by the additional substitution Ser 7→Lys, but the resulting analogue remained cytotoxic to erythrocytes (LC 50=38μm). 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=8μm) but appreciably lower haemolytic activity (LC 50=185μm) and cytotoxicity against A549 human alveolar basal epithelial cells (LC 50=65μm). The analogue shows potential for treatment of nosocomial pulmonary infections caused by bacteria that have developed resistance to commonly used antibiotics.

Original languageEnglish
Pages (from-to)270-275
Number of pages6
JournalJournal of Peptide Science
Volume18
Issue number4
DOIs
Publication statusPublished - Apr 2012

Keywords

  • Alyteserin-2a
  • Antimicrobial peptide
  • Gram-negative bacteria
  • Structure-activity

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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