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: Samir Attoub, Milena Mechkarska, Agnes Sonnevend, Gordana Radosavljevic, Ivan Jovanovic, Miodrag L Lukic, J Michael Conlon
• Journal: Peptides (Peptides) Vol. 39 Pg. 95-102 (Jan 2013) ISSN: 1873-5169 [Electronic] United States
• PMID: 23159562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Antimicrobial Cationic Peptides
• Antineoplastic Agents
• Cytokines
• Lipopolysaccharides
• esculentin-2CHa, Lithobates chiricahuensis

Topics

• Amino Acid Sequence
• Animals
• Anti-Bacterial Agents (pharmacology)
• Antimicrobial Cationic Peptides (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cytokines (metabolism)
• Erythrocytes (drug effects)
• Escherichia coli (drug effects)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Inhibitory Concentration 50
• Lipopolysaccharides (pharmacology)
• Macrophages, Peritoneal (drug effects, immunology, metabolism)
• Mice
• Microbial Sensitivity Tests
• Molecular Sequence Data
• Protein Structure, Secondary
• Ranidae
• Staphylococcus aureus (drug effects)