title: Esculentin-2CHa: a host-defense peptide with differential cytotoxicity against bacteria, erythrocytes and tumor cells.
abstract: The host-defense peptide, esculentin-2CHa (GFSSIFRGVA(10)KFASKGLGK D(20)LAKLGVDLVA(30) CKISKQC) shows potent (MIC≤6 μM) growth inhibitory activity against clinical isolates of multidrug-resistant strains of Staphylococcus aureus, Acinetobacter baumannii, and Stenotrophomonas maltophilia and differential cytotoxic activity against human erythrocytes (LC(50)=150 μM) and human non-small cell lung adenocarcinoma A549 cells (LC(50)=10 μM). Esculentin-2CHa significantly (P<0.01) stimulates the release of the anti-inflammatory cytokine IL-10 by mouse lymphoid cells and elevates its production after stimulation with concanavalin A and significantly (P<0.05) stimulates TNF-α production by peritoneal macrophages. Effects on IL-6 and IL-1β production were not significant. Removal of the hydrophobic N-terminal hexapeptide (GFSSIF) from esculentin-2CHa results in abolition of growth inhibitory activity against S. aureus and cytotoxic activity against erythrocytes and A549 cells as well as a marked (≥16-fold) reduction in potency against A. baumannii and S. maltophilia. The primary structure of esculentin-2 has been poorly conserved between frog species but evolutionary pressure has acted to maintain the hydrophobic character of this N-terminal hexapeptide sequence. Removal of the cyclic C-terminal domain (CKISKQC) and replacement of the Cys(31) and Cys(37) residues by serine resulted in appreciable decreases in cytotoxicity against all microorganisms and against mammalian cells. The more cationic [D20K, D27K] analog showed a modest increase in potency against all microorganisms (up to 4-fold) but a marked increase in cytotoxicity against erythrocytes (LC(50)=11 μM) and A549 cells (LC(50)=3 μM).
authors.affiliation: Department of Pharmacology, College of Medicine and Health Sciences, United Arab Emirates University, 17666 Al-Ain, United Arab Emirates.
authors.forename: Samir
authors.initials: S
authors.lastname: Attoub
authors.forename: Milena
authors.initials: M
authors.lastname: Mechkarska
authors.forename: Agnes
authors.initials: A
authors.lastname: Sonnevend
authors.forename: Gordana
authors.initials: G
authors.lastname: Radosavljevic
authors.forename: Ivan
authors.initials: I
authors.lastname: Jovanovic
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; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects*; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011898:Ranidae; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D016207:Cytokines; D008070:Lipopolysaccharides; C582446:esculentin-2CHa, Lithobates chiricahuensis