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

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• 作者：Milena Mechkarska ; Manju Prajeep ; Gordana D. Radosavljevic ; Ivan P. Jovanovic ; Amna Al Baloushi ; Agnes Sonnevend ; Miodrag L. Lukic ; J. Michael Conlon
• 关键词：Antimicrobial peptide ; Hymenochirin-1B ; Structure-activity ; MRSA ; Carbapenem-resistant Enterobacteriaceae ; Cytokine
• 刊名：Peptides
• 出版年：December, 2013
• 年：2013
• 卷：50
• 期：Complete
• 页码：153-159
• 全文大小：626 K

文摘

Hymenochirin-1B (IKLSPETKDN¹⁰LKKVLKGAIK²⁰GAIAVAKMV.NH₂) is a cationic, amphipathic, 伪-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, Glu⁶ and Asp⁹ on the hydrophilic face of the 伪-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 渭M) 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 渭M), and low hemolytic activity (LC₅₀ = 302 渭M). [E6k,D9k]hymenochirin-1B, at a concentration of 2.5 渭M, 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-伪 and IL-17.