{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:03:08Z","timestamp":1792040588057,"version":"4.4.0"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Research Council of New Zealand","award":["16\/232"],"award-info":[{"award-number":["16\/232"]}]},{"name":"Health Research Council of New Zealand","award":["19\/397"],"award-info":[{"award-number":["19\/397"]}]},{"name":"Sir John Walsh Research Institute","award":["16\/232"],"award-info":[{"award-number":["16\/232"]}]},{"name":"Sir John Walsh Research Institute","award":["19\/397"],"award-info":[{"award-number":["19\/397"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Aspergillus fumigatus is intrinsically resistant to the widely used antifungal fluconazole, and therapeutic failure can result from acquired resistance to voriconazole, the primary treatment for invasive aspergillosis. The molecular basis of substrate specificity and innate and acquired resistance of A. fumigatus to azole drugs were addressed using crystal structures, molecular models, and expression in Saccharomyces cerevisiae of the sterol 14\u03b1-demethylase isoforms AfCYP51A and AfCYP51B targeted by azole drugs, together with their cognate reductase AfCPRA2 and AfERG6 (sterol 24-C-methyltransferase). As predicted by molecular modelling, functional expression of CYP51A and B required eburicol and not lanosterol. A crowded conformationally sensitive region involving the BC-loop, helix I, and the heme makes AfCYP51A T289 primarily responsible for resistance to fluconazole, VT-1161, and the agrochemical difenoconazole. The Y121F T289A combination was required for higher level acquired resistance to fluconazole, VT-1161, difenoconazole, and voriconazole, and confirms posaconazole, isavuconazole and possibly ravuconazole as preferred treatments for target-based azole-resistant aspergillosis due to such a combination of mutations.<\/jats:p>","DOI":"10.3390\/jof10120820","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T05:06:53Z","timestamp":1732597613000},"page":"820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The Molecular Basis of the Intrinsic and Acquired Resistance to Azole Antifungals in Aspergillus fumigatus"],"prefix":"10.3390","volume":"10","author":[{"given":"Parham","family":"Hosseini","sequence":"first","affiliation":[{"name":"Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin 9016, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5193-6982","authenticated-orcid":false,"given":"Mikhail V.","family":"Keniya","sequence":"additional","affiliation":[{"name":"Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin 9016, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alia A.","family":"Sagatova","sequence":"additional","affiliation":[{"name":"Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin 9016, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0205-1666","authenticated-orcid":false,"given":"Stephanie","family":"Toepfer","sequence":"additional","affiliation":[{"name":"Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin 9016, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1163-2527","authenticated-orcid":false,"given":"Christoph","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research, Ludwig-Maximilian University Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0783-1635","authenticated-orcid":false,"given":"Joel D. 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