{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T13:56:01Z","timestamp":1767707761804,"version":"3.41.2"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T00:00:00Z","timestamp":1679356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Cryptococcus is the causal agent of cryptococcosis, a disease with high mortality mainly related to HIV immunosuppression and usually manifests with pneumonia and\/or meningoencephalitis. There are very few therapeutic options; thus, innovative approaches are required. Herein, We examined the interaction of everolimus (EVL) with amphotericin B (AmB) and azoles [fluconazole (FLU), posaconazole (POS), voriconazole (VOR), itraconazole (ITR)] against <jats:italic>Cryptococcus<\/jats:italic>. Eighteen <jats:italic>Cryptococcus neoforman<\/jats:italic> clinical isolates were analyzed. Following the guidelines of the Clinical and Laboratory Standards Institute (CLSI) M27-A4, we conducted a broth microdilution experiment to determine the minimum inhibitory concentrations (MICs) of azoles, EVL, and AmB for assessing antifungal susceptibility. A fractional inhibitory concentration index (FICI) of less than and equal to 0.5 indicated synergy, with a range of 0.5 to 4.0 indicated indifference and a value more than 4.0 indicated antagonism. These experiments revealed that EVL had antifungal activity against <jats:italic>C. neoforman<\/jats:italic>. Moreover, EVL, POS, AmB, FLU, ITR, and VOR exhibited MIC values ranging from 0.5-2 \u03bcg\/mL, 0.03125-2 \u03bcg\/mL, 0.25-4 \u03bcg\/mL, 0.5-32\u03bcg\/mL, 0.0625-4\u03bcg\/mL and 0.03125-2\u03bcg\/mL, respectively. The combination of EVL with AmB and azoles (POS, FLU, ITR, and VOR) exhibited synergistic antifungal effects against 16 (88.9%), 9 (50%), 11 (61.1%), 10 (55.6%) or 6 (33.3%) of analyzed <jats:italic>Cryptococcus<\/jats:italic> strains. In the presence of EVL, the MIC values of AmB and azoles were significantly lowered. No antagonism was observed. Subsequently, <jats:italic>in vivo<\/jats:italic> analyses conducted using the <jats:italic>G. mellonella<\/jats:italic> model further confirmed that combination EVL+ POS, EVL+ FLU, and EVL+ITR treatment were associated with significantly improved larval survival following <jats:italic>Cryptococcus<\/jats:italic> spp. infection. These findings provide the first published evidence suggesting that a combination of EVL and AmB or azoles exhibit a synergistic effect and may be an effective antifungal disease treatment strategy for infections caused by <jats:italic>Cryptococcus<\/jats:italic> spp.<\/jats:p>","DOI":"10.3389\/fcimb.2023.1131641","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T05:59:53Z","timestamp":1679378393000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Interactions between antifungals and everolimus against Cryptococcus neoformans"],"prefix":"10.3389","volume":"13","author":[{"given":"Pin","family":"Liang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiquan","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.00367","article-title":"Examining the virulence of candida albicans transcription factor mutants using galleria mellonella and mouse infection models","volume":"6","author":"Amorim-Vaz","year":"2015","journal-title":"Front. 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