{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T14:33:37Z","timestamp":1762353217947,"version":"3.41.2"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T00:00:00Z","timestamp":1656979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82102418, 82173429"],"award-info":[{"award-number":["82102418, 82173429"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["2019CFB567"],"award-info":[{"award-number":["2019CFB567"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014175","name":"Shanghai Municipal Health and Family Planning Commission","doi-asserted-by":"publisher","award":["201940476"],"award-info":[{"award-number":["201940476"]}],"id":[{"id":"10.13039\/501100014175","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["21Y11904900"],"award-info":[{"award-number":["21Y11904900"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Multiple cellular activities, including protein and lipid synthesis, ribosome biogenesis, and metabolic processes, are regulated by the target of rapamycin (TOR) pathway. Recent research suggests that the TOR might play an important role in various physiological functions of pathogenic fungi, such as nutrient sensing, stress response, and cell cycle progression. Given their robust immunosuppressant and antitumor activities, TOR inhibitors are widely used in clinical settings. In the present study, a microdilution checkerboard-based approach was employed to assess the interactions between the oral mammalian target of rapamycin (mTOR) inhibitor everolimus (EVL) and antifungal agents in the treatment of <jats:italic>Aspergillus<\/jats:italic> species derived from 35 clinical isolates <jats:italic>in vitro.<\/jats:italic> The results revealed that EVL exhibited promising inhibitory synergy with itraconazole (ITC), posaconazole (POS), and amphotericin B (AMB) for 85.7%, 74.2%, and 71.4%, respectively. In contrast, EVL exhibited minimal synergistic inhibitory activity (14.3%) when applied in combination with voriconazole (VRC). Antagonistic interactions were not observed. <jats:italic>In vivo<\/jats:italic> experiments conducted in <jats:italic>Galleria mellonella<\/jats:italic> revealed that EVL in combination with  antifungal agents improved the larva survival rates in the ITC, VRC, POS, and AMB groups by 18.3%, 13.3%, 26.7%, and 13.3%, respectively. These data suggest that the combination treatment with antifungal agents and antifungal agents holds promise as a means of alleviating clinical aspergillosis.<\/jats:p>","DOI":"10.3389\/fcimb.2022.936814","type":"journal-article","created":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T06:11:27Z","timestamp":1657001487000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["In Vitro Interactions of Antifungal Agents and Everolimus Against Aspergillus Species"],"prefix":"10.3389","volume":"12","author":[{"given":"Huiping","family":"Jiang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianqun","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lihua","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianjuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingwen","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.1002\/pmic.201400584","article-title":"Comparative Proteomics of a Tor Inducible Aspergillus Fumigatus Mutant Reveals Involvement of the Tor Kinase in Iron Regulation","volume":"15","author":"Baldin","year":"2015","journal-title":"Proteomics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.idc.2021.03.008","article-title":"Aspergillosis: Epidemiology, Diagnosis, and Treatment","volume":"35","author":"Cadena","year":"2021","journal-title":"Infect. Dis. Clin. North Am."},{"volume-title":"Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi. Approved Standard, 2nd Ed CLSI Document M38-A2","year":"2008","key":"B3"},{"key":"B4","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1128\/mmbr.66.4.579-591.2002","article-title":"Elucidating TOR Signaling and Rapamycin Action: Lessons From Saccharomyces Cerevisiae","volume":"66","author":"Crespo","year":"2002","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"547","DOI":"10.2165\/00003495-200666040-00009","article-title":"Everolimus: A Review of its Use in Renal and Cardiac Transplantation","volume":"66","author":"Dunn","year":"2006","journal-title":"Drugs"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1592\/phco.30.10.1044","article-title":"Everolimus: A Proliferation Signal Inhibitor With Clinical Applications in Organ Transplantation, Oncology, and Cardiology","volume":"30","author":"Gabardi","year":"2010","journal-title":"Pharmacotherapy"},{"key":"B7","doi-asserted-by":"publisher","first-page":"3813","DOI":"10.1128\/AAC.02921-15","article-title":"In Vitro Interactions Between Target of Rapamycin Kinase Inhibitor and Antifungal Agents Against Aspergillus Species","volume":"60","author":"Gao","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.01658","article-title":"INK128 Exhibits Synergy With Azoles Against Exophiala Spp. And Fusarium Spp","volume":"7","author":"Gao","year":"2016","journal-title":"Front. Microbiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/978-3-319-91442-8_8","article-title":"Everolimus","volume":"211","author":"Hasskarl","year":"2018","journal-title":"Recent Results Cancer Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1007\/s10096-002-0699-z","article-title":"Invasive Aspergillosis in 2002: An Update","volume":"21","author":"Kontoyiannis","year":"2002","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1093\/jac\/dkg090","article-title":"Combination of Caspofungin With Inhibitors of the Calcineurin Pathway Attenuates Growth In Vitro in Aspergillus Species","volume":"51","author":"Kontoyiannis","year":"2003","journal-title":"J. Antimicrob. Chemother."},{"key":"B12","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1055\/s-0039-3401990","article-title":"Invasive Pulmonary Aspergillosis","volume":"41","author":"Ledoux","year":"2020","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1186\/s13287-021-02206-y","article-title":"mTOR Inhibitor INK128 Promotes Wound Healing by Regulating MDSCs","volume":"12","author":"Li","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkg301","article-title":"Synergy, Antagonism, and What the Chequerboard Puts Between Them","volume":"52","author":"Odds","year":"2003","journal-title":"J. Antimicrob. Chemother."},{"key":"B15","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1586\/era.09.27","article-title":"Everolimus (RAD001): An mTOR Inhibitor for the Treatment of Metastatic Renal Cell Carcinoma","volume":"9","author":"Oudard","year":"2009","journal-title":"Expert Rev. Anticancer Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1038\/nport.2008.141","article-title":"A Simple and Reproducible 96-Well Plate-Based Method for the Formation of Fungal Biofilms and its Application to Antifungal Susceptibility Testing","volume":"3","author":"Pierce","year":"2018","journal-title":"Nat. Protoc."},{"key":"B17","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/j.riam.2018.07.001","article-title":"Invasive Aspergillosis in Critically Ill Patients","volume":"35","author":"Ramirez","year":"2018","journal-title":"Rev. Iberoam Micol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1080\/17434440.2020.1784005","article-title":"Durable Polymer Everolimus-Eluting Stents: History, Current Status and Future Prospects","volume":"17","author":"Rodr\u00edguez-Arias","year":"2020","journal-title":"Expert Rev. Med. Devices"},{"key":"B19","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/978-3-642-18930-2_4","article-title":"Nutrient Signaling Through TOR Kinases Controls Gene Expression and Cellular Differentiation in Fungi","volume":"279","author":"Rohde","year":"2004","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"7S","DOI":"10.1016\/s0041-1345(03)00211-2","article-title":"Sirolimus: its discovery, biological properties, and mechanism of action","volume":"35","author":"Sehgal","year":"2003","journal-title":"Transplant. Proc."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.trre.2021.100655","article-title":"An Overview of the Efficacy and Safety of Everolimus in Adult Solid Organ Transplant Recipients","volume":"36","author":"Tedesco-Silva","year":"2022","journal-title":"Transplant. Rev. (Orlando)"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1056\/NEJMra2027424","article-title":"Aspergillus Infections","volume":"385","author":"Thompson","year":"2021","journal-title":"N Engl. J. Med."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2021-245131","article-title":"Triple Infection With Disseminated Tuberculosis, Invasive Aspergillosis and COVID-19 in an Organ Transplant Recipient With Iatrogenic Immunosuppression","volume":"14","author":"Vidanapathirana","year":"2021","journal-title":"BMJ Case Rep."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.936814\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T06:11:32Z","timestamp":1657001492000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.936814\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,5]]},"references-count":23,"alternative-id":["10.3389\/fcimb.2022.936814"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.936814","relation":{},"ISSN":["2235-2988"],"issn-type":[{"type":"electronic","value":"2235-2988"}],"subject":[],"published":{"date-parts":[[2022,7,5]]},"article-number":"936814"}}