title: Antimicrobial effects of helix D-derived peptides of human antithrombin III.
abstract: Antithrombin III (ATIII) is a key antiproteinase involved in blood coagulation. Previous investigations have shown that ATIII is degraded by Staphylococcus aureus V8 protease, leading to release of heparin binding fragments derived from its D helix. As heparin binding and antimicrobial activity of peptides frequently overlap, we here set out to explore possible antibacterial effects of intact and degraded ATIII. In contrast to intact ATIII, the results showed that extensive degradation of the molecule yielded fragments with antimicrobial activity. Correspondingly, the heparin-binding, helix D-derived, peptide FFFAKLNCRLYRKANKSSKLV (FFF21) of human ATIII, was found to be antimicrobial against particularly the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa. Fluorescence microscopy and electron microscopy studies demonstrated that FFF21 binds to and permeabilizes bacterial membranes. Analogously, FFF21 was found to induce membrane leakage of model anionic liposomes. In vivo, FFF21 significantly reduced P. aeruginosa infection in mice. Additionally, FFF21 displayed anti-endotoxic effects in vitro. Taken together, our results suggest novel roles for ATIII-derived peptide fragments in host defense.
authors.affiliation: From the Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Tornavägen 10, SE-221 84 Lund, Sweden, the Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, Tornavägen 10, SE-221 84 Lund, Sweden, praveen.papareddy@med.lu.se.
authors.forename: Praveen
authors.initials: P
authors.lastname: Papareddy
authors.affiliation: From the Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Tornavägen 10, SE-221 84 Lund, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Kalle
authors.affiliation: the Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, Tornavägen 10, SE-221 84 Lund, Sweden.
authors.forename: Ravi K V
authors.initials: RK
authors.lastname: Bhongir
authors.affiliation: the Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, Tornavägen 10, SE-221 84 Lund, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: the Department of Pharmacy, Uppsala University, SE-751 23, Uppsala, Sweden, and.
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
authors.affiliation: From the Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Tornavägen 10, SE-221 84 Lund, Sweden, the LKCMedicine, Nanyang Technological University, 11 Mandalay Road, Singapore, 308232.
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D000990:Antithrombin III / Q000737:chemistry* / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002942:Circular Dichroism; D004195:Disease Models, Animal; D015844:Heparin Cofactor II / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D059748:Proteolysis / Q000187:drug effects; D011552:Pseudomonas Infections / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000890:Anti-Infective Agents; D008070:Lipopolysaccharides; D008081:Liposomes; D010455:Peptides; D015844:Heparin Cofactor II; D000990:Antithrombin III; D010196:Pancreatic Elastase
keywords: Antimicrobial; Antithrombin (AT); Antithrombin iii; Bacteria; Heparin; Membrane; Peptide; Sepsis