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Due to the increase in drug resistance and incidence of infections, there is an urgent need to develop new antifungals and to identify co-drugs that can sensitize drug-resistant Candida to antifungals. The objective of this study was to assess the effect of saquinavir on the activity of azole antifungals against C. auris. The in vitro interaction of saquinavir and three azole antifungals (itraconazole, voriconazole, and fluconazole) was evaluated against a panel of C. auris isolates. The itraconazole\/saquinavir combination exhibited a synergistic (SYN) relationship against all C. auris isolates tested with the fractional inhibitory concentration index ranging from 0.03 to 0.27. Moreover, a time-kill kinetics assay revealed that saquinavir restored the itraconazole\u2019s fungistatic activity against C. auris. Furthermore, saquinavir restored itraconazole\u2019s antifungal activity against other clinically important Candida species. The mechanistic investigation indicated that saquinavir significantly inhibited efflux pumps, glucose utilization, and ATP synthesis in Candida. Finally, a murine model of C. auris infection was used to evaluate the efficacy of the itraconazole\/saquinavir combination in the presence of ritonavir (as a pharmacokinetic enhancer). The combination significantly reduced the fungal burden in the kidneys by 0.93-log10 colony-forming units (88%) compared to itraconazole alone. This study identified that saquinavir exhibits a potent SYN relationship in combination with itraconazole against Candida species, which warrants further consideration.<\/jats:p>","DOI":"10.1093\/mmy\/myad081","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T00:50:44Z","timestamp":1691542244000},"source":"Crossref","is-referenced-by-count":13,"title":["Saquinavir potentiates itraconazole\u2019s antifungal activity against multidrug-resistant\n                    <i>Candida auris in vitro<\/i>\n                    and\n                    <i>in vivo<\/i>"],"prefix":"10.1093","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5735-9223","authenticated-orcid":false,"given":"Yehia","family":"Elgammal","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA"},{"name":"Center for One Health Research, Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehab A","family":"Salama","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA"},{"name":"Center for One Health Research, Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed N","family":"Seleem","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA"},{"name":"Center for One Health Research, Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,9]]},"reference":[{"key":"2023090712521483300_bib1","doi-asserted-by":"crossref","first-page":"e200430","DOI":"10.1590\/0074-02760200430","article-title":"Invasive fungal disease in humans: Are we aware of the real impact?","volume":"115","author":"Firacative","year":"2020","journal-title":"Mem. 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