{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T01:57:08Z","timestamp":1755223028496,"version":"3.43.0"},"reference-count":38,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mycoses"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Azoles target Cyp51A and Cyp51B in <jats:styled-content style=\"fixed-case\"><jats:italic>Aspergillus fumigatus<\/jats:italic><\/jats:styled-content>. Mutations in <jats:italic>cyp51A<\/jats:italic> are known as the primary mechanisms of azole resistance. However, not all of them cause azole resistance. Among them, mutations related to improved susceptibility have not been reported so far. We found that two isolates that carry frameshift or nonsense mutations in <jats:italic>cyp51A<\/jats:italic> are more susceptible to azoles, even to fluconazole (FLCZ) (IC<jats:sub>50<\/jats:sub>: frameshift, 32\u2009\u03bcg\/mL; nonsense, 32\u2009\u03bcg\/mL) compared to other azole\u2010susceptible strains (IC<jats:sub>50<\/jats:sub>: &gt;\u2009256\u2009\u03bcg\/mL).<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>We investigated the contribution of these two mutations to azole sensitivity and their effect on Cyp51A functions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We transformed an experimental strain, AfS35, by replacing <jats:italic>cyp51A<\/jats:italic><jats:sup>WT<\/jats:sup> with each of the mutated <jats:italic>cyp51A<\/jats:italic> and measured its MICs to azoles. We also evaluated the functions of mutated Cyp51A after suppression of Cyp51B, based on the notion that Cyp51A and Cyp51B complement each other.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Induction of mutated <jats:italic>cyp51A<\/jats:italic> in AfS35 led to higher susceptibility to FLCZ (IC<jats:sub>50<\/jats:sub>: frameshift, 32\u201364\u2009\u03bcg\/mL; nonsense, 32\u2009\u03bcg\/mL). Transformants carrying either of the mutated <jats:italic>cyp51A<\/jats:italic> could not survive when <jats:italic>cyp51B<\/jats:italic> was suppressed, indicating that these <jats:italic>cyp51A<\/jats:italic> mutations result in Cyp51A dysfunction. Furthermore, a <jats:italic>cyp51A<\/jats:italic>\u2010deleted mutant strain also showed increased susceptibility to FLCZ (IC<jats:sub>50<\/jats:sub>: 32\u2009\u03bcg\/mL), similar to <jats:italic>cyp51A<\/jats:italic> dysfunctional strains, while a <jats:italic>cyp51B\u2010<\/jats:italic>deleted mutant strain showed unchanged susceptibility (IC<jats:sub>50<\/jats:sub>: &gt;\u2009256\u2009\u03bcg\/mL) from AfS35.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>It was suggested that FLCZ can inhibit Cyp51B rather than Cyp51A and that this unequal inhibition leads to higher azole susceptibility of the two isolates harbouring Cyp51A dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.1111\/myc.70052","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T21:57:33Z","timestamp":1743803853000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>Cyp51A<\/scp> Dysfunction Leads to Higher Susceptibility to Azoles Including Fluconazole in <i>Aspergillus fumigatus<\/i>"],"prefix":"10.1111","volume":"68","author":[{"given":"Hidetaka","family":"Majima","sequence":"first","affiliation":[{"name":"Medical Mycology Research Center, Chiba University  Chiba Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teppei","family":"Arai","sequence":"additional","affiliation":[{"name":"Medical Mycology Research Center, Chiba University  Chiba Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoto","family":"Maruguchi","sequence":"additional","affiliation":[{"name":"Medical Mycology Research Center, Chiba University  Chiba Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuhiko","family":"Kamei","sequence":"additional","affiliation":[{"name":"Medical Mycology Research Center, Chiba University  Chiba Japan"},{"name":"Chiba Fuyo Hospital  Chiba 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