title: A Defensin from the Model Beetle Tribolium castaneum Acts Synergistically with Telavancin and Daptomycin against Multidrug Resistant Staphylococcus aureus.
abstract: The red flour beetle Tribolium castaneum is a common insect pest and has been established as a model beetle to study insect development and immunity. This study demonstrates that defensin 1 from T. castaneum displays in vitro and in vivo antimicrobial activity against drug resistant Staphylococcus aureus strains. The minimum inhibitory concentration (MIC) of defensin 1 against 11 reference and clinical staphylococcal isolates was between 16-64 μg/ml. The putative mode of action of the defensin peptide is disruption of the bacterial cell membrane. The antibacterial activity of defensin 1 was attenuated by salt concentrations of 1.56 mM and 25 mM for NaCl and CaCl2 respectively. Treatment of defensin 1 with the reducing agent dithiothreitol (DTT) at concentrations 1.56 to 3.13 mM abolished the antimicrobial activity of the peptide. In the presence of subinhibitory concentrations of antibiotics that also target the bacterial cell envelope such as telavancin and daptomycin, the MIC of the peptide was as low as 1 μg/ml. Moreover, when tested against an S. aureus strain that was defective in D-alanylation of the cell wall, the MIC of the peptide was 0.5 μg/ml. Defensin 1 exhibited no toxicity against human erythrocytes even at 400 μg/ml. The in vivo activity of the peptide was validated in a Caenorhabditis elegans-MRSA liquid infection assay. These results suggest that defensin 1 behaves similarly to other cationic AMPs in its mode of action against S. aureus and that the activity of the peptide can be enhanced in combination with other antibiotics with similar modes of action or with compounds that have the ability to decrease D-alanylation of the bacterial cell wall.
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, 02903, United States of America; Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, United States of America.
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Rajamuthiah
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, 02903, United States of America; Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, United States of America.
authors.forename: Elamparithi
authors.initials: E
authors.lastname: Jayamani
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, United States of America.
authors.forename: Annie L
authors.initials: AL
authors.lastname: Conery
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
authors.forename: Beth Burgwyn
authors.initials: BB
authors.lastname: Fuchs
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
authors.forename: Wooseong
authors.initials: W
authors.lastname: Kim
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Johnston
authors.affiliation: Institute of Phytopathology and Applied Zoology, Justus-Liebig University, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vilcinskas
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, United States of America.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Ausubel
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, 02903, United States of America; Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, United States of America.
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Mylonakis
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000382:microbiology; D002470:Cell Survival / Q000187:drug effects; D002473:Cell Wall / Q000187:drug effects; D002478:Cells, Cultured; D017576:Daptomycin / Q000494:pharmacology; D023082:Defensins / Q000378:metabolism* / Q000494:pharmacology*; D004357:Drug Synergism; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D019476:Insect Proteins / Q000378:metabolism / Q000494:pharmacology; D000077427:Lipoglycopeptides; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D014231:Tribolium / Q000378:metabolism*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D023082:Defensins; D019476:Insect Proteins; D000077427:Lipoglycopeptides; D017576:Daptomycin; C487637:telavancin