An analog of the host-defense peptide hymenochirin-1B with potent broad-spectrum activity against multidrug-resistant bacteria and immunomodulatory properties

Milena Mechkarska, Manju Prajeep, Gordana D. Radosavljevic, Ivan P. Jovanovic, Amna Al Baloushi, Agnes Sonnevend, Miodrag L. Lukic, J. Michael Conlon

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Hymenochirin-1B (IKLSPETKDN10LKKVLKGAIK20GAIAVAKMV. NH2) is a cationic, amphipathic, α-helical, host-defense peptide, first isolated from skin secretions of the Congo clawed frog Hymenochirus boettgeri (Pipidae). Structure-activity relationships were investigated by synthesizing analogs in which the Pro5, Glu 6 and Asp9 on the hydrophilic face of the α-helix are substituted by one or more l-lysine or d-lysine residues. Although replacement with l-lysine generates analogs with increased antimicrobial potency against a range of Gram-positive and Gram-negative bacteria (up to 8-fold), the peptides are more hemolytic. Increasing the cationicity of hymenochirin-1B while reducing the helicity by substitutions with d-lysine generates analogs that are between 2 and 8 fold more potent than the native peptide and are equally or less hemolytic. [E6k,D9k]hymenochirin-1B represents a candidate for drug development as it shows high potency against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and a range of Gram-negative bacteria, including multidrug-resistant strains of Acinetobacter baumannii and Stenotrophomonas maltophilia (MIC in the range 0.8-3.1 μM) and NDM-1 carbapenemase-producing clinical isolates of Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae and Citrobacter freundii (MIC in the range 3.1-6.25 μM), and low hemolytic activity (LC50 = 302 μM). [E6k,D9k]hymenochirin-1B, at a concentration of 2.5 μM, significantly (P < 0.05) stimulates the production of the anti-inflammatory cytokines IL-4 and IL-10 by human peripheral blood mononuclear cells but is without significant effect on production of the pro-inflammatory cytokines TNF-α and IL-17.

Original languageEnglish
Pages (from-to)153-159
Number of pages7
JournalPeptides
Volume50
DOIs
Publication statusPublished (in print/issue) - 2013

Bibliographical note

Funding Information:
This work was supported by a Faculty Support Grant ( NP-10-11/103 ) from the United Arab Emirates University ; the Terry Fox Fund for Cancer Research , and Ministry of Education and Science, Belgrade, Serbia (grants no 175071 , 175069 and 175103 ).

Keywords

  • Antimicrobial peptide
  • Carbapenem-resistant Enterobacteriaceae
  • Cytokine
  • Hymenochirin-1B
  • MRSA
  • Structure-activity

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