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Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species

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dc.contributor.authorEldesouky, Hassan E.en
dc.contributor.authorSalama, Ehab A.en
dc.contributor.authorLi, Xiaoyanen
dc.contributor.authorHazbun, Tony R.en
dc.contributor.authorMayhoub, Abdelrahman S.en
dc.contributor.authorSeleem, Mohamed N.en
dc.date.accessioned2020-09-21T16:12:39Zen
dc.date.available2020-09-21T16:12:39Zen
dc.date.issued2020-05-05en
dc.date.updated2020-09-21T16:12:37Zen
dc.description.abstractThe limited number of antifungals and the rising frequency of azole-resistant Candida species are growing challenges to human medicine. Drug repurposing signifies an appealing approach to enhance the activity of current antifungal drugs. Here, we evaluated the ability of Pharmakon 1600 drug library to sensitize an azole-resistant Candida albicans to the effect of fluconazole. The primary screen revealed 44 non-antifungal hits were able to act synergistically with fluconazole against the test strain. Of note, 21 compounds, showed aptness for systemic administration and limited toxic effects, were considered as potential fluconazole adjuvants and thus were termed as “repositionable hits”. A follow-up analysis revealed pitavastatin displaying the most potent fluconazole chemosensitizing activity against the test strain (ΣFICI 0.05) and thus was further evaluated against 18 isolates of C. albicans (n = 9), C. glabrata (n = 4), and C. auris (n = 5). Pitavastatin displayed broad-spectrum synergistic interactions with both fluconazole and voriconazole against ~89% of the tested strains (ΣFICI 0.05–0.5). Additionally, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of the tested Candida species by up to 73%, and successfully reduced the fungal burdens in a Caenorhabditis elegans infection model by up to 96%. This study presents pitavastatin as a potent azole chemosensitizing agent that warrant further investigation.en
dc.description.versionPublished versionen
dc.format.extent12 page(s)en
dc.format.mediumElectronicen
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 7525 (Article number)en
dc.identifier.doihttps://doi.org/10.1038/s41598-020-64571-7en
dc.identifier.eissn2045-2322en
dc.identifier.issn2045-2322en
dc.identifier.issue1en
dc.identifier.orcidSeleem, Mohamed [0000-0003-0939-0458]en
dc.identifier.other10.1038/s41598-020-64571-7 (PII)en
dc.identifier.pmid32372011 (pubmed)en
dc.identifier.urihttp://hdl.handle.net/10919/100027en
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.subjectANTIFUNGAL ACTIVITYen
dc.subjectSACCHAROMYCES-CEREVISIAEen
dc.subjectALBICANS STRAINSen
dc.subjectEFFLUX PUMPen
dc.subjectFLUCONAZOLEen
dc.subjectEXPRESSIONen
dc.subjectGENEen
dc.subjectMECHANISMSen
dc.subjectERGOSTEROLen
dc.subjectBIOFILMSen
dc.titleRepurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida speciesen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2020-03-04en
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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