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dc.contributor.authorBarbu, E. Magdaen_US
dc.contributor.authorShirazi, Fazalen_US
dc.contributor.authorMcGrath, Danielle M.en_US
dc.contributor.authorAlbert, Nathanielen_US
dc.contributor.authorSidman, Richard L.en_US
dc.contributor.authorPasqualini, Renataen_US
dc.contributor.authorArap, Wadihen_US
dc.contributor.authorKontoyiannis, Dimitrios P.en_US
dc.date.accessioned2014-03-10T20:34:30Z
dc.date.issued2013en_US
dc.identifier.citationBarbu, E. Magda, Fazal Shirazi, Danielle M. McGrath, Nathaniel Albert, Richard L. Sidman, Renata Pasqualini, Wadih Arap, and Dimitrios P. Kontoyiannis. 2013. “An Antimicrobial Peptidomimetic Induces Mucorales Cell Death through Mitochondria-Mediated Apoptosis.” PLoS ONE 8 (10): e76981. doi:10.1371/journal.pone.0076981. http://dx.doi.org/10.1371/journal.pone.0076981.en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11878963
dc.description.abstractThe incidence of mucormycosis has dramatically increased in immunocompromised patients. Moreover, the array of cellular targets whose inhibition results in fungal cell death is rather limited. Mitochondria have been mechanistically identified as central regulators of detoxification and virulence in fungi. Our group has previously designed and developed a proteolytically-resistant peptidomimetic motif D(KLAKLAK)2 with pleiotropic action ranging from targeted (i.e., ligand-directed) activity against cancer and obesity to non-targeted activity against antibiotic resistant gram-negative rods. Here we evaluated whether this non-targeted peptidomimetic motif is active against Mucorales. We show that D(KLAKLAK)2 has marked fungicidal action, inhibits germination, and reduces hyphal viability. We have also observed cellular changes characteristic of apoptosis in D(KLAKLAK)2-treated Mucorales cells. Moreover, the fungicidal activity was directly correlated with vacuolar injury, mitochondrial swelling and mitochondrial membrane depolarization, intracellular reactive oxygen species accumulation (ROS), and increased caspase-like enzymatic activity. Finally, these apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine indicating mechanistic pathway specificity. Together, these findings indicate that D(KLAKLAK)2 makes Mucorales exquisitely susceptible via mitochondrial injury-induced apoptosis. This prototype may serve as a candidate drug for the development of translational applications against mucormycosis and perhaps other fungal infections.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pone.0076981en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789667/pdf/en
dash.licenseLAAen_US
dc.titleAn Antimicrobial Peptidomimetic Induces Mucorales Cell Death through Mitochondria-Mediated Apoptosisen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS ONEen
dash.depositing.authorSidman, Richard L.en_US
dc.date.available2014-03-10T20:34:30Z
dc.identifier.doi10.1371/journal.pone.0076981*
dash.contributor.affiliatedSidman, Richard


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