Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs

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dc.contributor.authorEldesouky, Hassan E.en
dc.contributor.authorLanman, Nadia A.en
dc.contributor.authorHazbun, Tony R.en
dc.contributor.authorSeleem, Mohamed N.en
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.date.accessioned2021-09-01T12:34:34Zen
dc.date.available2021-09-01T12:34:34Zen
dc.date.issued2020-01-01en
dc.date.updated2021-09-01T12:34:30Zen
dc.description.abstractWith the rapid increase in the frequency of azole-resistant species, combination therapy appears to be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the effect of aprepitant, an antiemetic agent, on the antifungal activities of azole drugs against the multidrug-resistant Candida auris. Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro, by up to eight-folds. Additionally, the aprepitant/itraconazole combination interfered significantly with the biofilm-forming ability of C. auris by 95 ± 0.13%, and significantly disrupted mature biofilms by 52 ± 0.83%, relative to the untreated control. In a Caenorhabditis elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% (five days post-infection) and reduced the fungal burden by ~92% relative to the untreated control. Further, this novel drug combination displayed broad-spectrum synergistic interactions against other medically important Candida species such as C. albicans, C. krusei, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 0.31). Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris. This study presents aprepitant as a novel, potent, and broad-spectrum azole chemosensitizing agent that warrants further investigation.en
dc.description.versionPublished versionen
dc.format.extentPages 1466-1481en
dc.format.extent16 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1080/21505594.2020.1838741en
dc.identifier.eissn2150-5608en
dc.identifier.issn2150-5594en
dc.identifier.issue1en
dc.identifier.orcidSeleem, Mohamed [0000-0003-0939-0458]en
dc.identifier.pmid33100149en
dc.identifier.urihttp://hdl.handle.net/10919/104888en
dc.identifier.volume11en
dc.language.isoenen
dc.publisherTaylor & Francisen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000583577600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectLife Sciences & Biomedicineen
dc.subjectImmunologyen
dc.subjectInfectious Diseasesen
dc.subjectMicrobiologyen
dc.subjectCandida aurisen
dc.subjectfungal biofilmsen
dc.subjectazole resistanceen
dc.subjectCaenorhabditis elegansen
dc.subjectmetal ion homeostasisen
dc.subjectreactive oxygen species (ROS)en
dc.subjectALBICANS STRAINSen
dc.subjectANTIFUNGALen
dc.subjectIRONen
dc.subjectGENERATIONen
dc.subjectRESISTANCEen
dc.subjectDISCOVERYen
dc.subjectBIOFILMSen
dc.subjectPACKAGEen
dc.subject0501 Ecological Applicationsen
dc.subject0605 Microbiologyen
dc.subject1108 Medical Microbiologyen
dc.subject.meshAnimalsen
dc.subject.meshCaenorhabditis elegansen
dc.subject.meshBiofilmsen
dc.subject.meshCandidaen
dc.subject.meshCandidiasisen
dc.subject.meshIonsen
dc.subject.meshMetalsen
dc.subject.meshAzolesen
dc.subject.meshAntiemeticsen
dc.subject.meshAntifungal Agentsen
dc.subject.meshMicrobial Sensitivity Testsen
dc.subject.meshGene Expression Profilingen
dc.subject.meshDrug Resistance, Multiple, Fungalen
dc.subject.meshHomeostasisen
dc.subject.meshDrug Synergismen
dc.subject.meshAprepitanten
dc.titleAprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugsen
dc.title.serialVirulenceen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
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/CVM T&R Facultyen

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