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Current antifungal treatment primarily depends on the triazole antifungals, which act by inhibiting Erg11\/Cyp51, a key enzyme in the ergosterol biosynthetic pathway. However, resistance is emerging at an increasing rate, reducing treatment efficacy and patient survival. Confirmed resistance mechanisms in clinical isolates include mutations in\n cyp51A<\/jats:italic>\n ,\n cyp51B<\/jats:italic>\n ,\n hmg1<\/jats:italic>\n ,\n hapE<\/jats:italic>\n ,\n cox10<\/jats:italic>\n , and the overexpression of drug efflux pumps. To identify additional determinants of triazole resistance, we grew\n A. fumigatus<\/jats:italic>\n wild-type and\n \u0394cyp51A<\/jats:italic>\n mutant strains under increasing concentrations of voriconazole. Sequencing of the resultant resistant strains identified known mutations in\n cyp51A<\/jats:italic>\n and\n cyp51B<\/jats:italic>\n , and novel mutations in\n hmg1<\/jats:italic>\n ,\n abcC (cdr1B)<\/jats:italic>\n ,\n ptaB, erg25B,<\/jats:italic>\n and\n srbA<\/jats:italic>\n . Mutations of\n hmg1<\/jats:italic>\n and\n ptaB<\/jats:italic>\n occurred early during evolution, while mutations of\n erg25B<\/jats:italic>\n and\n srbA<\/jats:italic>\n occurred later. Reintroduction of the novel mutations in\n hmg1<\/jats:italic>\n ,\n abcC<\/jats:italic>\n ,\n ptaB,<\/jats:italic>\n and\n erg25B<\/jats:italic>\n into wild-type\n A. fumigatus<\/jats:italic>\n and correction of the\n srbA<\/jats:italic>\n mutation in the evolved strain validated their contribution toward triazole resistance. Sterol profiling analysis indicated that mutation or deletion of\n erg25B<\/jats:italic>\n is associated with a decrease in the accumulation of methylated sterols. Mutation or deletion of\n ptaB<\/jats:italic>\n resulted in increased\n cyp51A<\/jats:italic>\n ,\n cyp51B<\/jats:italic>\n , and\n erg25A<\/jats:italic>\n expression. Sequence analysis of clinical isolates revealed enrichment of missense mutations in\n ptaB<\/jats:italic>\n ,\n hmg1<\/jats:italic>\n ,\n abcC<\/jats:italic>\n , and\n srbA<\/jats:italic>\n among triazole-resistant strains.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1128\/aac.01635-25","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T15:10:30Z","timestamp":1772637030000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Directed evolution of the pathogenic mold\n Aspergillus fumigatus<\/i>\n reveals novel genes contributing to triazole resistance"],"prefix":"10.1128","volume":"70","author":[{"given":"Mariana","family":"Handelman","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04mhzgx49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Microbiology and Immunology, Gray School of Medicine, Tel Aviv University","place":["Tel Aviv, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argha","family":"Sarkar","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04mhzgx49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Microbiology and Immunology, Gray School of Medicine, Tel Aviv University","place":["Tel Aviv, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avital","family":"Varshavsky","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04mhzgx49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Microbiology and Immunology, Gray School of Medicine, Tel Aviv University","place":["Tel Aviv, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yona","family":"Shadkchan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04mhzgx49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Microbiology and Immunology, Gray School of Medicine, Tel Aviv University","place":["Tel Aviv, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02fa3aq29","id-type":"ROR","asserted-by":"publisher"}],"name":"David Braley Centre for Antibiotics Discovery, M.G. 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