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Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

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dc.contributor.authorThangamani, Shankaren
dc.contributor.authorMaland, Matthewen
dc.contributor.authorMohammad, Haroonen
dc.contributor.authorPascuzzi, Pete E.en
dc.contributor.authorAvramova, Larisaen
dc.contributor.authorKoehler, Carla M.en
dc.contributor.authorHazbun, Tony R.en
dc.contributor.authorSeleem, Mohamed N.en
dc.date.accessioned2020-09-21T16:13:13Zen
dc.date.available2020-09-21T16:13:13Zen
dc.date.issued2017-01-18en
dc.date.updated2020-09-21T16:13:10Zen
dc.description.abstractCurrent antifungal therapies have limited effectiveness in treating invasive fungal infections. Furthermore, the development of new antifungal is currently unable to keep pace with the urgent demand for safe and effective new drugs. Auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, inhibits growth of a diverse array of clinical isolates of fungi and represents a new antifungal agent with a previously unexploited mechanism of action. In addition to auranofin's potent antifungal activity against planktonic fungi, this drug significantly reduces the metabolic activity of Candida cells encased in a biofilm. Unbiased chemogenomic profiling, using heterozygous S. cerevisiae deletion strains, combined with growth assays revealed three probable targets for auranofin's antifungal activity-mia40, acn9, and coa4. Mia40 is of particular interest given its essential role in oxidation of cysteine rich proteins imported into the mitochondria. Biochemical analysis confirmed auranofin targets the Mia40-Erv1 pathway as the drug inhibited Mia40 from interacting with its substrate, Cmc1, in a dose-dependent manner similar to the control, MB-7. Furthermore, yeast mitochondria overexpressing Erv1 were shown to exhibit resistance to auranofin as an increase in Cmc1 import was observed compared to wild-type yeast. Further in vivo antifungal activity of auranofin was examined in a Caenorhabditis elegans animal model of Cryptococcus neoformans infection. Auranofin significantly reduced the fungal load in infected C. elegans. Collectively, the present study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antifungal agent and may offer a safe, effective, and quick supplement to current approaches for treating fungal infections.en
dc.description.versionPublished versionen
dc.format.extent13 page(s)en
dc.format.mediumElectronic-eCollectionen
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 4 (Article number)en
dc.identifier.doihttps://doi.org/10.3389/fcimb.2017.00004en
dc.identifier.eissn2235-2988en
dc.identifier.issn2235-2988en
dc.identifier.issueJANen
dc.identifier.orcidSeleem, Mohamed [0000-0003-0939-0458]en
dc.identifier.pmid28149831 (pubmed)en
dc.identifier.urihttp://hdl.handle.net/10919/100029en
dc.identifier.volume7en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectLife Sciences & Biomedicineen
dc.subjectImmunologyen
dc.subjectMicrobiologyen
dc.subjectauranofinen
dc.subjectantifungalen
dc.subjectrepurposingen
dc.subjectchemogenomic profilingen
dc.subjectMia40-Erv1 pathwayen
dc.subjectCANDIDA-ALBICANS BIOFILMSen
dc.subjectSMALL-MOLECULE INHIBITORen
dc.subjectDISULFIDE RELAY SYSTEMen
dc.subjectDRUG-RESISTANCEen
dc.subjectSTAPHYLOCOCCAL INFECTIONSen
dc.subjectIN-VITROen
dc.subjectSACCHAROMYCES-CEREVISIAEen
dc.subjectPROTEIN TRANSLOCATIONen
dc.subjectENTAMOEBA-HISTOLYTICAen
dc.subjectRHEUMATOID-ARTHRITISen
dc.subject0601 Biochemistry and Cell Biologyen
dc.subject0605 Microbiologyen
dc.subject.meshMitochondriaen
dc.subject.meshHumansen
dc.subject.meshBiofilmsen
dc.subject.meshReactive Oxygen Speciesen
dc.subject.meshAuranofinen
dc.subject.meshSaccharomyces cerevisiae Proteinsen
dc.subject.meshMitochondrial Membrane Transport Proteinsen
dc.subject.meshMitochondrial Proteinsen
dc.subject.meshAntifungal Agentsen
dc.subject.meshMicrobial Sensitivity Testsen
dc.subject.meshGene Expression Profilingen
dc.subject.meshSignal Transductionen
dc.subject.meshGene Expression Regulation, Fungalen
dc.subject.meshGene Deletionen
dc.subject.meshMembrane Potentialsen
dc.subject.meshOxygen Consumptionen
dc.subject.meshOxidoreductases Acting on Sulfur Group Donorsen
dc.subject.meshHaploinsufficiencyen
dc.subject.meshDrug Repositioningen
dc.titleRepurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathwayen
dc.title.serialFrontiers in Cellular and Infection Microbiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2017-01-03en
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen
pubs.organisational-group/Virginia Techen

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