{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:32:14Z","timestamp":1785407534757,"version":"3.56.0"},"reference-count":28,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272354"],"award-info":[{"award-number":["82272354"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,3,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The World Health Organization has flagged the rise of drug resistance in\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      as a critical concern. Elevated mutation rates in this pathogen contribute to the rapid development of resistance, complicating treatment efforts. We conducted a study on the prevalence of azole resistance among clinical\n                      <jats:italic toggle=\"yes\">A. fumigatus<\/jats:italic>\n                      isolates in the Netherlands from 1994 to 2022 and identified 34\n                      <jats:italic toggle=\"yes\">cyp51A<\/jats:italic>\n                      variants. To investigate the impact of individual single-nucleotide polymorphisms (SNPs) and combinations thereof on the azole phenotype in TR\n                      <jats:sub>34<\/jats:sub>\n                      -mediated resistance genotypes, we focused on novel, recent mutations and explored the effects of SNPs L98H, T289A, I364V, and G448S and the combination of the mutations TR\n                      <jats:sub>34<\/jats:sub>\n                      \/L98H, TR\n                      <jats:sub>34<\/jats:sub>\n                      \/L98H\/T289A\/G448S, and TR\n                      <jats:sub>34<\/jats:sub>\n                      \/L98H\/T289A\/I364V\/G448S on azole affinity and susceptibility. We created the three-dimensional protein model of the Cyp51A protein with azoles, and the mutation was introduced to the wild-type\n                      <jats:italic toggle=\"yes\">cyp51A A. fumigatus<\/jats:italic>\n                      strain by the CRISPR-Cas9 gene editing technique. Finally,\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      susceptibility testing of\n                      <jats:italic toggle=\"yes\">A. fumigatus<\/jats:italic>\n                      strains carrying the mutations was conducted to confirm the azole phenotypes observed in clinical isolates. The MICs of all four azoles against the mutated\n                      <jats:italic toggle=\"yes\">cyp51A<\/jats:italic>\n                      strains, which harbored combination mutations, were higher than those of the wild type, with highly elevated MICs of itraconazole, voriconazole, and isavuconazole. Genotypes TR\n                      <jats:sub>34<\/jats:sub>\n                      \/L98H\/T289A\/I364V\/G448S mutant showed a consistent phenotype to the clinical strains, which are highly resistant to voriconazole but susceptible to itraconazole. In this study, we show that molecular dynamics simulations of amino acid substitutions in the\n                      <jats:italic toggle=\"yes\">cyp51A<\/jats:italic>\n                      gene correlate to the structure\u2013function relationship of\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01528-25","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T14:37:31Z","timestamp":1770129451000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Characteristics of individual\n                    <i>cyp51A<\/i>\n                    SNPs and combinations thereof impacting the azole phenotype in TR\n                    <sub>34<\/sub>\n                    -mediated resistance genotypes of\n                    <i>Aspergillus fumigatus<\/i>"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1644-6942","authenticated-orcid":true,"given":"Yinggai","family":"Song","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02z1vqm45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Dermatology and Venerology, Peking University First Hospital","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/01yb10j39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center","place":["Nijmegen, the Netherlands"]},{"name":"Radboudumc-CWZ Center of Expertise for Mycology","place":["Nijmegen, the Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/02v51f717","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medical Mycology, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4031-0778","authenticated-orcid":true,"given":"Jochem B.","family":"Buil","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yb10j39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center","place":["Nijmegen, the Netherlands"]},{"name":"Radboudumc-CWZ Center of Expertise for Mycology","place":["Nijmegen, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Zoll","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yb10j39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center","place":["Nijmegen, the Netherlands"]},{"name":"Radboudumc-CWZ Center of Expertise for Mycology","place":["Nijmegen, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlou","family":"Tehupeiory-Kooreman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yb10j39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center","place":["Nijmegen, the Netherlands"]},{"name":"Radboudumc-CWZ Center of Expertise for Mycology","place":["Nijmegen, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanka","family":"Venselaar","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wg1m734","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical BioSciences, Radboudumc","place":["Nijmegen, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyu","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02z1vqm45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Dermatology and Venerology, Peking University First Hospital","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/02v51f717","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medical Mycology, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5446-2230","authenticated-orcid":true,"given":"Willem J. 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Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds. 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