title: An analog of the host-defense peptide hymenochirin-1B with potent broad-spectrum activity against multidrug-resistant bacteria and immunomodulatory properties.
abstract: Hymenochirin-1B (IKLSPETKDN(10)LKKVLKGAIK(20)GAIAVAKMV.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 Pro(5), Glu(6) and Asp(9) 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.
authors.affiliation: Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, 17666 Al-Ain, United Arab Emirates.
authors.forename: Milena
authors.initials: M
authors.lastname: Mechkarska
authors.forename: Manju
authors.initials: M
authors.lastname: Prajeep
authors.forename: Gordana D
authors.initials: GD
authors.lastname: Radosavljevic
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Jovanovic
authors.forename: Amna
authors.initials: A
authors.lastname: Al  Baloushi
authors.forename: Agnes
authors.initials: A
authors.lastname: Sonnevend
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
authors.forename: J Michael
authors.initials: JM
authors.lastname: Conlon
mesh_terms: D000595:Amino Acid Sequence; D029845:Amphibian Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002478:Cells, Cultured; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010884:Pipidae / Q000378:metabolism; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D029845:Amphibian Proteins; D023181:Antimicrobial Cationic Peptides; C508609:IL10 protein, human; C508598:IL4 protein, human; D007155:Immunologic Factors; D016753:Interleukin-10; D015847:Interleukin-4
keywords: Antimicrobial peptide; Carbapenem-resistant Enterobacteriaceae; Cytokine; Hymenochirin-1B; MRSA; Structure-activity