Ospemifene displays broad-spectrum synergistic interactions with itraconazole through potent interference with fungal efflux activities

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dc.contributor.authorEldesouky, Hassan E.en
dc.contributor.authorSalama, Ehab A.en
dc.contributor.authorHazbun, Tony R.en
dc.contributor.authorMayhoub, Abdelrahman S.en
dc.contributor.authorSeleem, Mohamed N.en
dc.date.accessioned2020-09-21T16:14:29Zen
dc.date.available2020-09-21T16:14:29Zen
dc.date.issued2020-04-08en
dc.date.updated2020-09-21T16:14:26Zen
dc.description.abstractAzole antifungals are vital therapeutic options for treating invasive mycotic infections. However, the emergence of azole-resistant isolates combined with limited therapeutic options presents a growing challenge in medical mycology. To address this issue, we utilized microdilution checkerboard assays to evaluate nine stilbene compounds for their ability to interact synergistically with azole drugs, particularly against azole-resistant fungal isolates. Ospemifene displayed the most potent azole chemosensitizing activity, and its combination with itraconazole displayed broad-spectrum synergistic interactions against Candida albicans, Candida auris, Cryptococcus neoformans, and Aspergillus fumigatus (ΣFICI = 0.05–0.50). Additionally, in a Caenorhabditis elegans infection model, the ospemifene-itraconazole combination significantly reduced fungal CFU burdens in infected nematodes by ~75–96%. Nile Red efflux assays and RT-qPCR analysis suggest ospemifene interferes directly with fungal efflux systems, thus permitting entry of azole drugs into fungal cells. This study identifies ospemifene as a novel antifungal adjuvant that augments the antifungal activity of itraconazole against a broad range of fungal pathogens.en
dc.description.versionPublished versionen
dc.format.extent10 page(s)en
dc.format.mediumElectronicen
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 6089 (Article number)en
dc.identifier.doihttps://doi.org/10.1038/s41598-020-62976-yen
dc.identifier.eissn2045-2322en
dc.identifier.issn2045-2322en
dc.identifier.issue1en
dc.identifier.orcidSeleem, Mohamed [0000-0003-0939-0458]en
dc.identifier.other10.1038/s41598-020-62976-y (PII)en
dc.identifier.pmid32269301 (pubmed)en
dc.identifier.urihttp://hdl.handle.net/10919/100032en
dc.identifier.volume10en
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectCANDIDA-ALBICANS STRAINSen
dc.subjectAZOLE RESISTANCEen
dc.subjectIN-VITROen
dc.subjectINVASIVE CANDIDIASISen
dc.subjectANTIFUNGAL ACTIVITYen
dc.subjectAMPHOTERICIN-Ben
dc.subjectCHALLENGESen
dc.subjectCASPOFUNGINen
dc.subjectFLUCONAZOLEen
dc.subjectPREVALENCEen
dc.titleOspemifene displays broad-spectrum synergistic interactions with itraconazole through potent interference with fungal efflux activitiesen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2020-03-19en
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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