Lopinavir and ritonavir act synergistically with azoles against Candida auris in vitro and in a mouse model of disseminated candidiasis

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dc.contributor.authorSalama, Ehab A.en
dc.contributor.authorEldesouky, Hassan E.en
dc.contributor.authorElgammal, Yehiaen
dc.contributor.authorAbutaleb, Nader S.en
dc.contributor.authorSeleem, Mohamed N.en
dc.date.accessioned2023-11-30T13:47:54Zen
dc.date.available2023-11-30T13:47:54Zen
dc.date.issued2023-09en
dc.description.abstractIntroduction and Objectives: The emergence of Candida auris has created a global health challenge. Azole antifungals are the most affected antifungal class because of the extraordinary capability of C. auris to develop resistance against these drugs. Here, we used a combinatorial therapeutic approach to sensitize C. auris to azole antifungals. Methods and Results: We have demonstrated the capability of the HIV protease inhibitors lopinavir and ritonavir, at clinically relevant concentrations, to be used with azole antifungals to treat C. auris infections both in vitro and in vivo. Both lopinavir and ritonavir exhibited potent synergistic interactions with the azole antifungals, particularly with itraconazole against 24/24 (100%) and 31/34 (91%) of tested C. auris isolates, respectively. Furthermore, ritonavir significantly interfered with the fungal efflux pump, resulting in a significant increase in Nile red fluorescence by 44%. In a mouse model of C. auris systemic infection, ritonavir boosted the activity of lopinavir to work synergistically with fluconazole and itraconazole and significantly reduced the kidney fungal burden by a 1.2 log (∼94%) and 1.6 log (∼97%) CFU, respectively. Conclusion: Our results urge further comprehensive assessment of azoles and HIV protease inhibitors as a novel drug regimen for the treatment of serious invasive C. auris infections.en
dc.description.versionAccepted versionen
dc.format.extent5 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 106906 (Article number)en
dc.identifier.doihttps://doi.org/10.1016/j.ijantimicag.2023.106906en
dc.identifier.eissn1872-7913en
dc.identifier.issn0924-8579en
dc.identifier.issue3en
dc.identifier.orcidSeleem, Mohamed [0000-0003-0939-0458]en
dc.identifier.otherS0924-8579(23)00185-1 (PII)en
dc.identifier.pmid37392947en
dc.identifier.urihttps://hdl.handle.net/10919/116710en
dc.identifier.volume62en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/37392947en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectHIV protease inhibitorsen
dc.subjectCandida aurisen
dc.subjectCheckerboard assayen
dc.subjectAzole resistanceen
dc.subjectIn vivo infection modelen
dc.subject.meshAnimalsen
dc.subject.meshMiceen
dc.subject.meshCandidiasisen
dc.subject.meshAzolesen
dc.subject.meshItraconazoleen
dc.subject.meshRitonaviren
dc.subject.meshHIV Protease Inhibitorsen
dc.subject.meshAntifungal Agentsen
dc.subject.meshMicrobial Sensitivity Testsen
dc.subject.meshDrug Resistance, Fungalen
dc.subject.meshLopinaviren
dc.subject.meshCandida aurisen
dc.titleLopinavir and ritonavir act synergistically with azoles against <i>Candida auris</i> in vitro and in a mouse model of disseminated candidiasisen
dc.title.serialInternational Journal of Antimicrobial Agentsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2023-06-25en
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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