{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:34:41Z","timestamp":1785429281639,"version":"3.56.0"},"reference-count":147,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/Y034473\/1"],"award-info":[{"award-number":["MR\/Y034473\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"award":["MR\/Y034473\/1"],"award-info":[{"award-number":["MR\/Y034473\/1"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Project Management Agency of the Germen Aerospace Center","award":["01KI2403"],"award-info":[{"award-number":["01KI2403"]}]},{"name":"Joint Programming Initiative on Antimicrobial Resistance consortium","award":["10570162310003"],"award-info":[{"award-number":["10570162310003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Aspergillus fumigatus is a leading cause of invasive fungal disease in humans and is classified as a critical priority threat by the World Health Organization. Triazole antifungals remain the cornerstone of therapy, yet their effectiveness is steadily being eroded by the continuous rise in drug resistance. Most resistance mechanisms trace back to mutations in Cyp51A, spawning well-defined genotypes such as TR34\/L98H and TR46\/Y121F\/T289A. However, the Cyp51A genotype\u2013phenotype landscape in A. fumigatus is far from straightforward. Isolates that share an identical TR genotype can display strikingly divergent susceptibility profiles, and mutational hotspots in Cyp51A, such as G54, M220 and G448, are linked to varying resistances, challenging assumptions about predictable resistance behavior. Complicating matters further, an expanding array of resistance mechanisms, independent of Cyp51A, is now being uncovered. This review summarizes the current state of knowledge on azole resistance in A. fumigatus, dissecting the intricate genotype\u2013phenotype relationships, spotlighting emerging non-Cyp51A pathways and outlining future strategies to enhance the detection and clinical management of antifungal resistance.<\/jats:p>","DOI":"10.3390\/jof12040290","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:24:23Z","timestamp":1776673463000},"page":"290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genotype\u2013Phenotype Relationships in Azole-Resistant Aspergillus: Two Sides of the Same Coin"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2281-8834","authenticated-orcid":false,"given":"Merlijn H. I.","family":"van Haren","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology, Radboudumc Community for Infectious Diseases, Radboudumc, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5446-2230","authenticated-orcid":false,"given":"Willem J. G.","family":"Melchers","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboudumc Community for Infectious Diseases, Radboudumc, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboudumc Community for Infectious Diseases, Radboudumc, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3821-1762","authenticated-orcid":false,"given":"Sarah","family":"Delli\u00e8re","sequence":"additional","affiliation":[{"name":"Parasitology-Mycology Department, H\u00f4pital Saint-Louis Paris, Assistance Publique-H\u00f4pitaux de Paris, 75010 Paris, France"},{"name":"Immunology of Fungal Infection, Institut Pasteur, Universit\u00e9 de Paris Cit\u00e9, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5635-3871","authenticated-orcid":false,"given":"Christine C.","family":"Bii","sequence":"additional","affiliation":[{"name":"Mycology Division, Center for Microbiology Research, Kenya Medical Research Institute, Nairobi P.O. Box 54840 00200, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia A.","family":"Stanford","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Nottingham, Nottingham NG7 2TQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Voetz","sequence":"additional","affiliation":[{"name":"Xebios Diagnostics GmbH, 40597 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3056-4205","authenticated-orcid":false,"given":"P. Lewis","family":"White","sequence":"additional","affiliation":[{"name":"Mycology Reference Laboratory, Public Health Wales, Cardiff CF14 4XW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0237-026X","authenticated-orcid":false,"given":"Paul S.","family":"Dyer","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Nottingham, Nottingham NG7 2TQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1943-1217","authenticated-orcid":false,"given":"Suzan D.","family":"Pas","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboudumc Community for Infectious Diseases, Radboudumc, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8600-9860","authenticated-orcid":false,"given":"Paul E.","family":"Verweij","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboudumc Community for Infectious Diseases, Radboudumc, 6525 GA Nijmegen, The Netherlands"},{"name":"Radboudumc-CWZ Center of Expertise for Mycology (RCEM), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4031-0778","authenticated-orcid":false,"given":"Jochem B.","family":"Buil","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboudumc Community for Infectious Diseases, Radboudumc, 6525 GA Nijmegen, The Netherlands"},{"name":"Radboudumc-CWZ Center of Expertise for Mycology (RCEM), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bongomin, F., Gago, S., Oladele, R.O., and Denning, D.W. 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