{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T13:07:19Z","timestamp":1780319239808,"version":"3.54.1"},"reference-count":39,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T00:00:00Z","timestamp":1721001600000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mycoses"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The resistance of <jats:italic>Aspergillus flavus<\/jats:italic> to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals \u2010 CYP 51 A, B and C \u2010 are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of resistant strains in\u00a0vitro and in\u00a0vivo is not yet understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>This study had 3 objectives. The first was to compare the sequences of <jats:italic>CYP51 A, B<\/jats:italic> and <jats:italic>C<\/jats:italic> in resistant and susceptible strains of <jats:italic>A. flavus<\/jats:italic>. The second was to look for the existence of a fitness cost associated with resistance. The third was to evaluate the activity of voriconazole and posaconazole on resistant strains in the <jats:italic>Galleria mellonella<\/jats:italic> model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The <jats:italic>CYP51 A, B<\/jats:italic> and <jats:italic>C<\/jats:italic> sequences of seven resistant strains with those of four susceptible strains are compared. Fitness costs were assessed by growing the strains in RPMI medium and testing their virulence in <jats:italic>G. mellonella<\/jats:italic> larvae. In addition, <jats:italic>G. mellonella<\/jats:italic> larvae infected with strains of <jats:italic>A. flavus<\/jats:italic> were treated with voriconazole and posaconazole.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the <jats:italic>CYP51A<\/jats:italic> sequences, we found the A91T, C708T and A1296T nucleotide substitutions only in the resistant strains. The resistant strains showed a fitness cost with reduced in\u00a0vitro growth and reduced virulence in <jats:italic>G. mellonella<\/jats:italic>. In\u00a0vivo resistance to posaconazole is confirmed in a strain with the highest MIC for this antifungal agent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results allow to conclude that some substitutions in <jats:italic>CYP51<\/jats:italic> genes, in particular <jats:italic>CYP51A<\/jats:italic>, contribute to resistance to azole drugs in <jats:italic>A. flavus<\/jats:italic>. The study of the relationship between drug dosage and treatment duration with resistance and the reduction of fitness costs in resistant strains is a major perspective of this study. This work could help to establish recommendations for the treatment of infections with resistant strains of <jats:italic>A. flavus.<\/jats:italic><\/jats:p><\/jats:sec>","DOI":"10.1111\/myc.13766","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T12:25:26Z","timestamp":1721046326000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Azole resistance in <i>Aspergillus flavus<\/i> and associated fitness cost"],"prefix":"10.1111","volume":"67","author":[{"given":"Elie","family":"Djenontin","sequence":"first","affiliation":[{"name":"Unit\u00e9 de Parasitologie\u2010Mycologie, D\u00e9partement de Virologie, Bact\u00e9riologie\u2010Hygi\u00e8ne, Parasitologie\u2010Mycologie CHU Henri Mondor, AP\u2010HP  Cr\u00e9teil France"},{"name":"UR Dynamyc UPEC, EnvA, ANSES. Facult\u00e9 de Sant\u00e9 de Cr\u00e9teil  Cr\u00e9teil France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Debourgogne","sequence":"additional","affiliation":[{"name":"UR7300 Stress Immunit\u00e9 Pathog\u00e8ne, Universit\u00e9 de Lorraine  Vandoeuvre les Nancy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bita","family":"Mousavi","sequence":"additional","affiliation":[{"name":"UR Dynamyc UPEC, EnvA, ANSES. Facult\u00e9 de Sant\u00e9 de Cr\u00e9teil  Cr\u00e9teil France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Delhaes","sequence":"additional","affiliation":[{"name":"CHU de Bordeaux: Laboratoire de Parasitologie\u2010Mycologie, CNR des Aspergilloses Chroniques, INSERM U1045: Univ. Bordeaux  Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muriel","family":"Cornet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, CNRS, Grenoble INP, CHU Grenoble Alpes, TIMC  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Valsecchi","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Parasitologie\u2010Mycologie, D\u00e9partement de Virologie, Bact\u00e9riologie\u2010Hygi\u00e8ne, Parasitologie\u2010Mycologie CHU Henri Mondor, AP\u2010HP  Cr\u00e9teil France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiath","family":"Adebo","sequence":"additional","affiliation":[{"name":"UR Dynamyc UPEC, EnvA, ANSES. Facult\u00e9 de Sant\u00e9 de Cr\u00e9teil  Cr\u00e9teil France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3577-6979","authenticated-orcid":false,"given":"Jacques","family":"Guillot","sequence":"additional","affiliation":[{"name":"Oniris, VetAgroBio Nantes  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Botterel","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Parasitologie\u2010Mycologie, D\u00e9partement de Virologie, Bact\u00e9riologie\u2010Hygi\u00e8ne, Parasitologie\u2010Mycologie CHU Henri Mondor, AP\u2010HP  Cr\u00e9teil France"},{"name":"UR Dynamyc UPEC, EnvA, ANSES. Facult\u00e9 de Sant\u00e9 de Cr\u00e9teil  Cr\u00e9teil France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Dannaoui","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Parasitologie\u2010Mycologie, D\u00e9partement de Virologie, Bact\u00e9riologie\u2010Hygi\u00e8ne, Parasitologie\u2010Mycologie CHU Henri Mondor, AP\u2010HP  Cr\u00e9teil France"},{"name":"Unit\u00e9 de Parasitologie\u2010Mycologie, Service de Microbiologie, H\u00f4pital Necker, AP\u2010HP  Paris France"},{"name":"Universit\u00e9 Paris Cit\u00e9 Facult\u00e9 de M\u00e9decine  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2027424"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.simyco.2020.05.002"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/jof5030055"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.2007\/007641-0"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fbr.2020.10.003"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2007.11.005"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.39.7.2431-2438.2001"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00691"},{"issue":"10","key":"e_1_2_8_10_1","first-page":"1217","article-title":"Point mutations in the 14\u2010a sterol demethylase Cyp51A or Cyp51C could contribute to azole resistance in aspergillus flavus","volume":"11","author":"Lucio J","year":"2020","journal-title":"Gen"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05477-11"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01022-18"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00637-15"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01928-17"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01610-18"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/jof7030164"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjid.2017.10.005"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/myc.13193"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.001480"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mycmed.2020.100953"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/jof6040296"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01594-15"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11102429"},{"key":"e_1_2_8_24_1","article-title":"Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds","volume":"9","author":"Arendrup MC","year":"2017","journal-title":"EUCAST Definitive Document EDef"},{"key":"e_1_2_8_25_1","unstructured":"The European Committee on Antimicrobial Susceptibility Testing.Overview of Antifungal ECOFFs and Clinical Breakpoints for Yeasts Moulds and Dermatophytes Using the EUCAST E.Def 7.3 E.Def 9.4 and E.Def 11.0 Procedures. Version 3. Available online:http:\/\/wwweucastorg(accessed on 1 September 2023). 2022"},{"issue":"41","key":"e_1_2_8_26_1","first-page":"95","article-title":"BioEdit: a user\u2010friendly biological sequence alignment editor and analysis program for windows 95\/98\/NT","volume":"41","author":"Hall TA","year":"1999","journal-title":"Nucleic Acids Symp Ser"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010080"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2021.1893945"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms8030390"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.1038342"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00095-16"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2008.06.018"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2013.04.022"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01216-18"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2012.07.008"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01491-16"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/jof7121012"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/mmy\/myx109"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00720-1"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2015.0460"}],"container-title":["Mycoses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/myc.13766","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T04:56:14Z","timestamp":1722228974000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/myc.13766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7]]},"references-count":39,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["10.1111\/myc.13766"],"URL":"https:\/\/doi.org\/10.1111\/myc.13766","archive":["Portico"],"relation":{},"ISSN":["0933-7407","1439-0507"],"issn-type":[{"value":"0933-7407","type":"print"},{"value":"1439-0507","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7]]},"assertion":[{"value":"2024-03-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13766"}}