{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:48:14Z","timestamp":1784162894401,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2019YFA0906600"],"award-info":[{"award-number":["2019YFA0906600"]}]},{"name":"National Key Research and Development Program of China","award":["21907074"],"award-info":[{"award-number":["21907074"]}]},{"name":"National Key Research and Development Program of China","award":["20JCQNJC02090"],"award-info":[{"award-number":["20JCQNJC02090"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2019YFA0906600"],"award-info":[{"award-number":["2019YFA0906600"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21907074"],"award-info":[{"award-number":["21907074"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["20JCQNJC02090"],"award-info":[{"award-number":["20JCQNJC02090"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Tianjin","award":["2019YFA0906600"],"award-info":[{"award-number":["2019YFA0906600"]}]},{"name":"Natural Science Foundation of Tianjin","award":["21907074"],"award-info":[{"award-number":["21907074"]}]},{"name":"Natural Science Foundation of Tianjin","award":["20JCQNJC02090"],"award-info":[{"award-number":["20JCQNJC02090"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Fungal infections pose a serious and growing threat to public health. These infections can be treated with antifungal drugs by killing hazardous fungi in the body. However, the resistance can develop over time when fungi are exposed to antifungal drugs by generating genomic variations, including mutation, aneuploidy, and loss of heterozygosity. The variations could reduce the binding affinity of a drug to its target or block the pathway through which drugs exert their activity. Here, we review genomic variation-mediating fluconazole resistance in the yeast Candida, with the hope of highlighting the functional consequences of genomic variations for the antifungal resistance.<\/jats:p>","DOI":"10.3390\/biom12060845","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T11:45:44Z","timestamp":1655466344000},"page":"845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Genomic Variation-Mediating Fluconazole Resistance in Yeast"],"prefix":"10.3390","volume":"12","author":[{"given":"Wen-Yao","family":"Wang","sequence":"first","affiliation":[{"name":"Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Qing","family":"Cai","sequence":"additional","affiliation":[{"name":"Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Yuan","family":"Qu","sequence":"additional","affiliation":[{"name":"Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Hao","family":"Lin","sequence":"additional","affiliation":[{"name":"Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Cheng","family":"Liang","sequence":"additional","affiliation":[{"name":"Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Liu","sequence":"additional","affiliation":[{"name":"Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Xiong","family":"Xie","sequence":"additional","affiliation":[{"name":"Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Jin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bongomin, F., Gago, S., Oladele, R.O., and Denning, D.W. (2017). Global and multi-national prevalence of fungal diseases-estimate precision. J. Fungi, 3.","DOI":"10.3390\/jof3040057"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.3389\/fmicb.2019.00214","article-title":"The still underestimated problem of fungal diseases worldwide","volume":"10","author":"Almeida","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bhattacharya, S., Sae-Tia, S., and Fries, B.C. (2020). Candidiasis and mechanisms of antifungal resistance. Antibiotics, 9.","DOI":"10.3390\/antibiotics9060312"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Costa-de-Oliveira, S., and Rodrigues, A.G. (2020). Candida albicans antifungal resistance and tolerance in bloodstream infections: The triad yeast-host-antifungal. Microorganisms, 8.","DOI":"10.3390\/microorganisms8020154"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1128\/MMBR.00045-10","article-title":"Regulatory circuitry governing fungal development, drug resistance, and disease","volume":"75","author":"Shapiro","year":"2011","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"237","DOI":"10.2147\/IDR.S118892","article-title":"Fluconazole resistance in Candida species: A current perspective","volume":"10","author":"Berkow","year":"2017","journal-title":"Infect. Drug Resist."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"a019752","DOI":"10.1101\/cshperspect.a019752","article-title":"Mechanisms of antifungal drug resistance","volume":"5","author":"Cowen","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e01585-21","DOI":"10.1128\/Spectrum.01585-21","article-title":"Delineation of the direct contribution of Candida auris ERG11 mutations to clinical triazole resistance","volume":"9","author":"Rybak","year":"2021","journal-title":"Microbiol. Spectr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1128\/AAC.05720-11","article-title":"Azole resistance by loss of function of the sterol delta(5,6)-desaturase gene (ERG3) in Candida albicans does not necessarily decrease virulence","volume":"56","author":"Coste","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3578","DOI":"10.1128\/AAC.00303-10","article-title":"A clinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14 alpha-demethylase) and ERG5 (encoding c22 desaturase) is cross resistant to azoles and amphotericin B","volume":"54","author":"Martel","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"575.e1","DOI":"10.1016\/j.cmi.2017.02.002","article-title":"Impact of ERG3 mutations and expression of ergosterol genes controlled by UPC2 and NDT80 in Candida parapsilosis azole resistance","volume":"23","author":"Branco","year":"2017","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1002\/iid3.415","article-title":"The effects of secreted aspartyl proteinase inhibitor ritonavir on azoles-resistant strains of Candida albicans as well as regulatory role of SAP2 and ERG11","volume":"9","author":"Feng","year":"2021","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/yea.3527","article-title":"UPC2 gene deletion modifies sterol homeostasis and susceptibility to metabolic inhibitors in Kluyveromyces lactis","volume":"37","author":"Hervay","year":"2020","journal-title":"Yeast"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"foy038","DOI":"10.1093\/femsyr\/foy038","article-title":"Sequence modification of the master regulator Pdr1 interferes with its transcriptional autoregulation and confers altered azole resistance in Candida glabrata","volume":"18","author":"Tian","year":"2018","journal-title":"FEMS Yeast Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.resmic.2019.08.005","article-title":"FLO8 deletion leads to azole resistance by upregulating CDR1 and CDR2 in Candida albicans","volume":"170","author":"Li","year":"2019","journal-title":"Res. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1111\/myc.12756","article-title":"CgPDR1 gain-of-function mutations lead to azole-resistance and increased adhesion in clinical Candida glabrata strains","volume":"61","author":"Ni","year":"2018","journal-title":"Mycoses"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1128\/EC.00245-13","article-title":"Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence","volume":"13","author":"Lohberger","year":"2014","journal-title":"Eukaryot. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00968-18","DOI":"10.1128\/AAC.00968-18","article-title":"Candida albicans zn cluster transcription factors Tac1 and Znc1 are activated by farnesol to upregulate a transcriptional program including the multidrug efflux pump CDR1","volume":"62","author":"Liu","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1126\/science.1128242","article-title":"Aneuploidy and isochromosome formation in drug-resistant Candida albicans","volume":"313","author":"Selmecki","year":"2006","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1093\/molbev\/msz104","article-title":"Aneuploidy enables cross-adaptation to unrelated drugs","volume":"36","author":"Yang","year":"2019","journal-title":"Mol. Biol. Evol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1021\/acs.chemrev.0c00199","article-title":"Antifungal drug resistance: Molecular mechanisms in Candida albicans and beyond","volume":"121","author":"Lee","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1128\/AAC.36.12.2602","article-title":"Characterization of an azole-resistant Candida glabrata isolate","volume":"36","author":"Marichal","year":"1992","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kwon-Chung, K.J., and Chang, Y.C. (2012). Aneuploidy and drug resistance in pathogenic fungi. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1003022"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1099\/mic.0.000478","article-title":"A chromosome 4 trisomy contributes to increased fluconazole resistance in a clinical isolate of Candida albicans","volume":"163","author":"Anderson","year":"2017","journal-title":"Microbiology"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Selmecki, A.M., Dulmage, K., Cowen, L.E., Anderson, J.B., and Berman, J. (2009). Acquisition of aneuploidy provides increased fitness during the evolution of antifungal drug resistance. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000705"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1111\/j.1365-2958.2008.06309.x","article-title":"Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains","volume":"69","author":"Dunkel","year":"2008","journal-title":"Mol. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1080\/13693780500138971","article-title":"An update on antifungal targets and mechanisms of resistance in Candida albicans","volume":"43","author":"Akins","year":"2005","journal-title":"Med. Mycol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1371\/journal.ppat.0030164","article-title":"The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans","volume":"3","author":"Morschhauser","year":"2007","journal-title":"PLoS Pathog."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00723-21","DOI":"10.1128\/Spectrum.00723-21","article-title":"Adaptation to fluconazole via aneuploidy enables cross-adaptation to amphotericin B and flucytosine in Cryptococcus neoformans","volume":"9","author":"Yang","year":"2021","journal-title":"Microbiol. Spectr."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Harrison, B.D., Hashemi, J., Bibi, M., Pulver, R., Bavli, D., Nahmias, Y., Wellington, M., Sapiro, G., and Berman, J. (2014). A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. PLoS Biol., 12.","DOI":"10.1371\/journal.pbio.1001815"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e00433-20","DOI":"10.1128\/mSphere.00433-20","article-title":"Host-Induced genome instability rapidly generates phenotypic variation across Candida albicans strains and ploidy states","volume":"5","author":"Smith","year":"2020","journal-title":"mSphere"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4019","DOI":"10.1534\/g3.119.400752","article-title":"The magnitude of Candida albicans stress-induced genome instability results from an interaction between ploidy and antifungal drugs","volume":"9","author":"Avramovska","year":"2019","journal-title":"Genes Genomes Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e00129-11","DOI":"10.1128\/mBio.00129-11","article-title":"Stress alters rates and types of loss of heterozygosity in Candida albicans","volume":"2","author":"Forche","year":"2011","journal-title":"mBio"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/nature10795","article-title":"Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy","volume":"482","author":"Chen","year":"2012","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s12275-016-5628-4","article-title":"The development of fluconazole resistance in Candida albicans\u2014An example of microevolution of a fungal pathogen","volume":"54","author":"Morschhauser","year":"2016","journal-title":"J. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1111\/j.1365-2958.2012.08210.x","article-title":"The stepwise acquisition of fluconazole resistance mutations causes a gradual loss of fitness in Candida albicans","volume":"86","author":"Sasse","year":"2012","journal-title":"Mol. Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e00662","DOI":"10.7554\/eLife.00662","article-title":"The evolution of drug resistance in clinical isolates of Candida albicans","volume":"4","author":"Ford","year":"2015","journal-title":"eLife"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e02740-18","DOI":"10.1128\/mBio.02740-18","article-title":"Evolution of fluconazole-resistant Candida albicans strains by drug-induced mating competence and parasexual recombination","volume":"10","author":"Popp","year":"2019","journal-title":"mBio"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1128\/EC.00151-07","article-title":"Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates","volume":"6","author":"Coste","year":"2007","journal-title":"Eukaryot. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1099\/mic.0.035154-0","article-title":"PAP1 poly(A) polymerase 1 homozygosity and hyperadenylation are major determinants of increased mRNA stability of CDR1 in azole-resistant clinical isolates of Candida albicans","volume":"156","author":"Manoharlal","year":"2010","journal-title":"Microbiology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"28191","DOI":"10.1073\/pnas.2018633117","article-title":"Genome-wide mapping of spontaneous genetic alterations in diploid yeast cells","volume":"117","author":"Sui","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Liang, S.H., and Bennett, R.J. (2020). The impact of gene dosage and heterozygosity on the diploid pathobiont Candida albicans. J. Fungi, 6.","DOI":"10.3390\/jof6010010"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1099\/00221287-148-4-1061","article-title":"Homozygosity at the Candida albicans MTL locus associated with azole resistance","volume":"148","author":"Rustad","year":"2002","journal-title":"Microbiology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nrg.2017.49","article-title":"Evolutionary biology through the lens of budding yeast comparative genomics","volume":"18","author":"Marsit","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1128\/AAC.50.4.1365-1371.2006","article-title":"Overexpression of the MDR1 gene is sufficient to confer increased resistance to toxic compounds in Candida albicans","volume":"50","author":"Hiller","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/nature16134","article-title":"The \u2018obligate diploid\u2019 Candida albicans forms mating-competent haploids","volume":"530","author":"Hickman","year":"2016","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"a019604","DOI":"10.1101\/cshperspect.a019604","article-title":"Rapid mechanisms for generating genome diversity: Whole ploidy shifts, aneuploidy, and loss of heterozygosity","volume":"4","author":"Bennett","year":"2014","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1128\/iai.00328-21","article-title":"Host defense mechanisms induce genome instability leading to rapid evolution in an opportunistic fungal pathogen","volume":"90","author":"Smith","year":"2022","journal-title":"Infect. Immun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e00167-17","DOI":"10.1128\/mSphere.00167-17","article-title":"Adaptive mistranslation accelerates the evolution of fluconazole resistance and induces major genomic and gene expression alterations in Candida albicans","volume":"2","author":"Weil","year":"2017","journal-title":"mSphere"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1534\/genetics.111.137927","article-title":"High-resolution genome-wide analysis of irradiated (uv and gamma-rays) diploid yeast cells reveals a high frequency of genomic loss of heterozygosity (LOH) events","volume":"190","author":"Yin","year":"2012","journal-title":"Genetics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1093\/nar\/gky1216","article-title":"Allele-specific genome editing using CRISPR-Cas9 is associated with loss of heterozygosity in diploid yeast","volume":"47","author":"Couwenberg","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s11427-019-9504-5","article-title":"Loss of heterozygosity by SCRaMbLEing","volume":"62","author":"Li","year":"2019","journal-title":"Sci. China Life Sci."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/6\/845\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:33:56Z","timestamp":1760139236000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/6\/845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,17]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["biom12060845"],"URL":"https:\/\/doi.org\/10.3390\/biom12060845","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,17]]}}}