{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:45:06Z","timestamp":1791726306665,"version":"4.3.4"},"reference-count":120,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T00:00:00Z","timestamp":1591660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health (NIH)","award":["NIH 1R01AI127704"],"award-info":[{"award-number":["NIH 1R01AI127704"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Candidiasis can be present as a cutaneous, mucosal or deep-seated organ infection, which is caused by more than 20 types of Candida sp., with C. albicans being the most common. These are pathogenic yeast and are usually present in the normal microbiome. High-risk individuals are patients of human immunodeficiency virus\/acquired immunodeficiency syndrome (HIV\/AIDS), organ transplant, and diabetes. During infection, pathogens can adhere to complement receptors and various extracellular matrix proteins in the oral and vaginal cavity. Oral and vaginal Candidiasis results from the overgrowth of Candida sp. in the hosts, causing penetration of the oral and vaginal tissues. Symptoms include white patches in the mouth, tongue, throat, and itchiness or burning of genitalia. Diagnosis involves visual examination, microscopic analysis, or culturing. These infections are treated with a variety of antifungals that target different biosynthetic pathways of the pathogen. For example, echinochandins target cell wall biosynthesis, while allylamines, azoles, and morpholines target ergosterol biosynthesis, and 5-Flucytosine (5FC) targets nucleic acid biosynthesis. Azoles are commonly used in therapeutics, however, because of its fungistatic nature, Candida sp. evolve azole resistance. Besides azoles, Candida sp. also acquire resistance to polyenes, echinochandins, and 5FC. This review discusses, in detail, the drug resistance mechanisms adapted by Candida sp.<\/jats:p>","DOI":"10.3390\/antibiotics9060312","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T08:49:11Z","timestamp":1591692551000},"page":"312","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":426,"title":["Candidiasis and Mechanisms of Antifungal Resistance"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8562-3877","authenticated-orcid":false,"given":"Somanon","family":"Bhattacharya","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Stony Brook University, Stony Brook, New York, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sutthichai","family":"Sae-Tia","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Stony Brook University, Stony Brook, New York, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6847-5518","authenticated-orcid":false,"given":"Bettina C.","family":"Fries","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Stony Brook University, Stony Brook, New York, NY 11794, USA"},{"name":"Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, NY 11794, USA"},{"name":"Veterans Administration Medical Center, Northport, New York, NY 11768, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1128\/CMR.00029-06","article-title":"Epidemiology of Invasive Candidiasis: A Persistent Public Health Problem","volume":"20","author":"Pfaller","year":"2007","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","unstructured":"Preventions, C.f.D.C.a. (2020, June 09). DRUG-RESISTANT CANDIDA SPECIES, Available online: https:\/\/www.cdc.gov\/drugresistance\/pdf\/threats-report\/candida-508.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.diagmicrobio.2012.10.003","article-title":"Epidemiology and outcomes of candidemia in 3648 patients: Data from the Prospective Antifungal Therapy (PATH Alliance\u00ae) registry, 2004\u20132008","volume":"74","author":"Pfaller","year":"2012","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1128\/CMR.17.2.255-267.2004","article-title":"Candida Infections of Medical Devices","volume":"17","author":"Kojic","year":"2004","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1093\/cid\/civ1194","article-title":"Executive Summary: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America","volume":"62","author":"Pappas","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kodedov\u00e1, M., and Sychrov\u00e1, H. (2015). Changes in the Sterol Composition of the Plasma Membrane Affect Membrane Potential, Salt Tolerance and the Activity of Multidrug Resistance Pumps in Saccharomyces cerevisiae. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139306"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e01291-18","DOI":"10.1128\/mBio.01291-18","article-title":"Overexpression or Deletion of Ergosterol Biosynthesis Genes Alters Doubling Time, Response to Stress Agents, and Drug Susceptibility inSaccharomyces cerevisiae","volume":"9","author":"Bhattacharya","year":"2018","journal-title":"mBio"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e00507-18","DOI":"10.1128\/AAC.00507-18","article-title":"Effect of Cumulative Intravenous Voriconazole Dose on Renal Function in Hematological Patients","volume":"62","author":"Yasu","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.2147\/DDDT.S145545","article-title":"Spotlight on isavuconazole in the treatment of invasive aspergillosis and mucormycosis: Design, development, and place in therapy","volume":"12","author":"Jenks","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.2147\/TCRM.S90335","article-title":"Role of isavuconazole in the treatment of invasive fungal infections","volume":"12","author":"Wilson","year":"2016","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"163","DOI":"10.2147\/IDR.S51340","article-title":"Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections","volume":"6","author":"Pasqualotto","year":"2013","journal-title":"Infect. Drug Resist."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S1567-1356(03)00126-0","article-title":"Combined overexpression of genes of the ergosterol biosynthetic pathway leads to accumulation of sterols in Saccharomyces cerevisiae","volume":"4","author":"Veen","year":"2003","journal-title":"FEMS Yeast Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"77","DOI":"10.4155\/fmc.13.189","article-title":"Reactive oxygen species-inducing antifungal agents and their activity against fungal biofilms","volume":"6","author":"Delattin","year":"2014","journal-title":"Future Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"67","DOI":"10.32607\/20758251-2014-6-4-67-79","article-title":"Investigation of Channel-Forming Activity of Polyene Macrolide Antibiotics in Planar Lipid Bilayers in the Presence of Dipole Modifiers","volume":"6","author":"Efimova","year":"2014","journal-title":"Acta Nat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s40265-013-0069-4","article-title":"Amphotericin B Formulations: A Comparative Review of Efficacy and Toxicity","volume":"73","author":"Hamill","year":"2013","journal-title":"Drugs"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1093\/jac\/dkl141","article-title":"Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion","volume":"57","author":"Vogelsinger","year":"2006","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1111\/j.1567-1364.2009.00578.x","article-title":"Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation","volume":"9","author":"Sanglard","year":"2009","journal-title":"FEMS Yeast Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"710","DOI":"10.4103\/0250-474X.49088","article-title":"Treatment of Onychomycosis: An Update","volume":"70","author":"Shirwaikar","year":"2008","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1080\/mmy.39.1.111.121","article-title":"The yeast cell-wall salvage pathway","volume":"39","author":"Popolo","year":"2001","journal-title":"Med. Mycol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"441","DOI":"10.2217\/fmb.11.19","article-title":"Current perspectives on echinocandin class drugs","volume":"6","author":"Perlin","year":"2011","journal-title":"Future Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1080\/mmy.39.1.55.66","article-title":"Fungal beta(1,3)-D-glucan synthesis","volume":"39","author":"Douglas","year":"2001","journal-title":"Med. Mycol."},{"key":"ref_22","first-page":"66","article-title":"Fungal echinocandin resistance","volume":"2","author":"Munro","year":"2010","journal-title":"F1000 Boil. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1086\/596757","article-title":"Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America","volume":"48","author":"Pappas","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1093\/jac\/46.2.171","article-title":"Flucytosine: A review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions","volume":"46","author":"Vermes","year":"2000","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5858","DOI":"10.1128\/AAC.01252-16","article-title":"A Combination Fluorescence Assay Demonstrates Increased Efflux Pump Activity as a Resistance Mechanism in Azole-Resistant Vaginal Candida albicans Isolates","volume":"60","author":"Bhattacharya","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1128\/CMR.11.2.382","article-title":"Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance","volume":"11","author":"White","year":"1998","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/AAC.39.1.1","article-title":"Resistance of Candida species to fluconazole","volume":"39","author":"Rex","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1128\/AAC.41.7.1482","article-title":"Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus","volume":"41","author":"White","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","first-page":"10","article-title":"Oral mucositis caused byCandida glabratabiofilms: Failure of the concomitant use of fluconazole and ascorbic acid","volume":"4","author":"Rodrigues","year":"2017","journal-title":"Ther. Adv. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"94","DOI":"10.2165\/00002018-199005020-00003","article-title":"Amphotericin B Nephrotoxicity","volume":"5","author":"Sabra","year":"1990","journal-title":"Drug Saf."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Faustino, C., and Pinheiro, L. (2020). Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12010029"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"37561","DOI":"10.1074\/jbc.M306137200","article-title":"The Antifungal Drug Amphotericin B Promotes Inflammatory Cytokine Release by a Toll-like Receptor- and CD14-dependent Mechanism","volume":"278","author":"Sau","year":"2003","journal-title":"J. Boil. Chem."},{"key":"ref_33","first-page":"283","article-title":"Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status","volume":"129","author":"Re","year":"2015","journal-title":"Am. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S604","DOI":"10.1093\/cid\/civ814","article-title":"Echinocandins: The Expanding Antifungal Armamentarium","volume":"61","author":"Petraitiene","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1128\/EC.00091-07","article-title":"Characterization of Three Classes of Membrane Proteins Involved in Fungal Azole Resistance by Functional Hyperexpression in Saccharomyces cerevisiae","volume":"6","author":"Lamping","year":"2007","journal-title":"Eukaryot. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Khandelwal, N.K., Wasi, M., Nair, R., Gupta, M., Kumar, M., Mondal, A.K., Gaur, N.A., and Prasad, R. (2019). Vacuolar Sequestration of Azoles, a Novel Strategy of Azole Antifungal Resistance Conserved across Pathogenic and Nonpathogenic Yeast. Antimicrob. Agents Chemother., 63.","DOI":"10.1128\/AAC.01347-18"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/j.1460-2075.1995.tb06989.x","article-title":"An ABC transporter in the mitochondrial inner membrane is required for normal growth of yeast","volume":"14","author":"Leighton","year":"1995","journal-title":"EMBO J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/S0014-5793(97)01414-2","article-title":"The ABC transporter Atm1p is required for mitochondrial iron homeostasis","volume":"418","author":"Kispal","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1101\/SQB.1995.060.01.034","article-title":"Sequence Comparison of Yeast ATP-binding Cassette Proteins","volume":"60","author":"Michealis","year":"1995","journal-title":"Cold Spring Harb. Symp. Quant. Boil."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1128\/CMR.00051-08","article-title":"Efflux-Mediated Antifungal Drug Resistance","volume":"22","author":"Cannon","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0968-0004(93)90081-W","article-title":"A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport","volume":"18","author":"Marger","year":"1993","journal-title":"Trends Biochem. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1128\/AAC.46.6.1704-1713.2002","article-title":"Resistance Mechanisms in Clinical Isolates of Candida albicans","volume":"46","author":"White","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1128\/AAC.00926-08","article-title":"Relative Contributions of the Candida albicans ABC Transporters Cdr1p and Cdr2p to Clinical Azole Resistance","volume":"53","author":"Tsao","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1099\/00221287-146-11-2743","article-title":"A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole","volume":"146","author":"Calabrese","year":"2000","journal-title":"Microbiology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1128\/EC.5.1.180-191.2006","article-title":"Cellular and Molecular Biology of Candida albicans Estrogen Response","volume":"5","author":"Cheng","year":"2006","journal-title":"Eukaryot. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1042\/BSR20080071","article-title":"Membrane homoeostasis and multidrug resistance in yeast","volume":"28","author":"Panwar","year":"2008","journal-title":"Biosci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1111\/j.1365-2958.2006.05196.x","article-title":"PDR16-mediated azole resistance in Candida albicans","volume":"60","author":"Saidane","year":"2006","journal-title":"Mol. Microbiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1128\/EC.00245-13","article-title":"Distinct Roles of Candida albicans Drug Resistance Transcription FactorsTAC1,MRR1, andUPC2in Virulence","volume":"13","author":"Lohberger","year":"2013","journal-title":"Eukaryot. Cell"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Morschh\u00e4user, J., Barker, K.S., Liu, T.T., Bla\u00df-Warmuth, J., Homayouni, R., and Rogers, P.D. (2007). The Transcription Factor Mrr1p Controls Expression of the MDR1 Efflux Pump and Mediates Multidrug Resistance in Candida albicans. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030164"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.1534\/genetics.105.054767","article-title":"A Mutation in Tac1p, a Transcription Factor Regulating CDR1 and CDR2, Is Coupled With Loss of Heterozygosity at Chromosome 5 to Mediate Antifungal Resistance in Candida albicans","volume":"172","author":"Coste","year":"2006","journal-title":"Genetics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1111\/j.1365-2958.2008.06309.x","article-title":"Mutations in the multi-drug resistance regulatorMRR1, followed by loss of heterozygosity, are the main cause ofMDR1overexpression in fluconazole-resistantCandida albicansstrains","volume":"69","author":"Dunkel","year":"2008","journal-title":"Mol. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"609","DOI":"10.5578\/mb.10105","article-title":"[Investigation of mutations in transcription factors of efflux pump genes in fluconazole-resistant Candida albicans strains overexpressing the efflux pumps]","volume":"49","author":"Kalkandelen","year":"2015","journal-title":"Mikrobiyoloji Bulteni"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4274","DOI":"10.1128\/AAC.00740-08","article-title":"Gain-of-Function Mutations in the Transcription Factor MRR1 Are Responsible for Overexpression of the MDR1 Efflux Pump in Fluconazole-Resistant Candida dubliniensis Strains","volume":"52","author":"Schubert","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4505","DOI":"10.1128\/AAC.48.12.4505-4512.2004","article-title":"CaNdt80 Is Involved in Drug Resistance in Candida albicans by Regulating CDR1","volume":"48","author":"Chen","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1128\/JB.181.1.231-240.1999","article-title":"Isolation of a Putative Candida albicansTranscriptional Regulator Involved in Pleiotropic Drug Resistance by Functional Complementation of a pdr1 pdr3 Mutation inSaccharomyces cerevisiae","volume":"181","author":"Talibi","year":"1999","journal-title":"J. Bacteriol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1128\/AAC.01467-10","article-title":"Differential Requirement of the Transcription Factor Mcm1 for Activation of the Candida albicans Multidrug Efflux PumpMDR1by Its Regulators Mrr1 and Cap1","volume":"55","author":"Mogavero","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1128\/JB.181.3.700-708.1999","article-title":"The bZip Transcription Factor Cap1p Is Involved in Multidrug Resistance and Oxidative Stress Response inCandida albicans","volume":"181","author":"Alarco","year":"1999","journal-title":"J. Bacteriol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1128\/AAC.49.2.668-679.2005","article-title":"Mechanisms of Azole Resistance in Clinical Isolates of Candida glabrata Collected during a Hospital Survey of Antifungal Resistance","volume":"49","author":"Sanguinetti","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3773","DOI":"10.1128\/AAC.48.10.3773-3781.2004","article-title":"Azole Resistance in Candida glabrata: Coordinate Upregulation of Multidrug Transporters and Evidence for a Pdr1-Like Transcription Factor","volume":"48","author":"Vermitsky","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.micres.2015.03.004","article-title":"Stress response and expression of fluconazole resistance associated genes in the pathogenic yeast Candida glabrata deleted in the CgPDR16 gene","volume":"174","author":"Culakova","year":"2015","journal-title":"Microbiol. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e02227-17","DOI":"10.1128\/AAC.02227-17","article-title":"Enhanced Efflux Pump Activity in OldCandida glabrataCells","volume":"62","author":"Bhattacharya","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3389\/fphys.2014.00197","article-title":"MFS multidrug transporters in pathogenic fungi: Do they have real clinical impact?","volume":"5","author":"Costa","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.3389\/fmicb.2016.00526","article-title":"Clotrimazole Drug Resistance in Candida glabrata Clinical Isolates Correlates with Increased Expression of the Drug:H+ Antiporters CgAqr1, CgTpo1_1, CgTpo3, and CgQdr2","volume":"7","author":"Costa","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Ferrari, S., Ischer, F., Calabrese, D., Posteraro, B., Sanguinetti, M., Fadda, G., Rohde, B., Bauser, C., Bader, O., and Sanglard, D. (2009). Gain of Function Mutations in CgPDR1 of Candida glabrata Not Only Mediate Antifungal Resistance but Also Enhance Virulence. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000268"},{"key":"ref_65","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_66","doi-asserted-by":"crossref","first-page":"e00065-15","DOI":"10.1128\/mSphere.00065-15","article-title":"Upregulation of the Adhesin Gene EPA1 Mediated by PDR1 in Candida glabrata Leads to Enhanced Host Colonization","volume":"1","author":"Moeckli","year":"2016","journal-title":"mSphere"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1128\/AAC.00811-12","article-title":"Candida glabrata Drug:H+Antiporter CgQdr2 Confers Imidazole Drug Resistance, Being Activated by Transcription Factor CgPdr1","volume":"57","author":"Costa","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1128\/AAC.01095-08","article-title":"Abc1p is a Multidrug Efflux Transporter That Tips the Balance in Favor of Innate Azole Resistance in Candida krusei","volume":"53","author":"Lamping","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1080\/13693780600561544","article-title":"Fluconazole resistance mechanisms inCandida krusei: The contribution of efflux-pumps","volume":"44","author":"Guinea","year":"2006","journal-title":"Med. Mycol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Zhang, L., Xiao, M., Watts, M.R., Wang, H., Fan, X., Kong, F., and Xu, Y.-C. (2015). Development of fluconazole resistance in a series of Candida parapsilosis isolates from a persistent candidemia patient with prolonged antifungal therapy. BMC Infect. Dis., 15.","DOI":"10.1186\/s12879-015-1086-6"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1042\/BST20051210","article-title":"Azole susceptibility and resistance in Candida dubliniensis","volume":"33","author":"Moran","year":"2005","journal-title":"Biochem. Soc. Trans."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"5052","DOI":"10.1038\/s41598-019-41513-6","article-title":"Gene Duplication Associated with Increased Fluconazole Tolerance in Candida auris cells of Advanced Generational Age","volume":"9","author":"Bhattacharya","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.3389\/fmicb.2019.02788","article-title":"Review on Antifungal Resistance Mechanisms in the Emerging Pathogen Candida auris","volume":"10","author":"Chaabane","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Rybak, J.M., Mu\u00f1oz, J.F., Barker, K.S., Parker, J.E., Esquivel, B.D., Berkow, E.L., Lockhart, S.R., Gade, L., Palmer, G.E., and White, T.C. (2020). Mutations in TAC1B: A Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris. mBio, 11.","DOI":"10.1128\/mBio.00365-20"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3332","DOI":"10.1128\/JCM.37.10.3332-3337.1999","article-title":"Quantitation of Ergosterol Content: Novel Method for Determination of Fluconazole Susceptibility of Candida albicans","volume":"37","author":"Jradi","year":"1999","journal-title":"J. Clin. Microbiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1128\/EC.00215-12","article-title":"Gain-of-Function Mutations inUPC2Are a Frequent Cause ofERG11Upregulation in Azole-Resistant Clinical Isolates of Candida albicans","volume":"11","author":"Flowers","year":"2012","journal-title":"Eukaryot. Cell"},{"key":"ref_77","first-page":"84","article-title":"Fluconazole susceptibility and ERG11 gene expression in vaginal candida species isolated from lagos Nigeria","volume":"3","author":"Pam","year":"2012","journal-title":"Int. J. Mol. Epidemiol. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1111\/1567-1364.12042","article-title":"Erg11mutations associated with azole resistance in clinical isolates ofCandida albicans","volume":"13","author":"Xiang","year":"2013","journal-title":"FEMS Yeast Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1590\/0074-02760150400","article-title":"Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species","volume":"111","author":"Silva","year":"2016","journal-title":"Mem\u00f3rias do Instituto Oswaldo Cruz"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1128\/AAC.06253-11","article-title":"Facultative Sterol Uptake in an Ergosterol-Deficient Clinical Isolate of Candida glabrata Harboring a Missense Mutation inERG11and Exhibiting Cross-Resistance to Azoles and Amphotericin B","volume":"56","author":"Hull","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3646","DOI":"10.1128\/AAC.49.9.3646-3651.2005","article-title":"Inactivation of Sterol \u03945,6-Desaturase Attenuates Virulence in Candida albicans","volume":"49","author":"Chau","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/S0014-5793(96)01360-9","article-title":"Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol delta5,6-desaturation","volume":"400","author":"Kelly","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1128\/AAC.47.8.2404-2412.2003","article-title":"Candida albicans Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents","volume":"47","author":"Sanglard","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.phrp.2010.12.009","article-title":"Gene Expression and Identification Related to Fluconazole Resistance of Candida glabrata Strains","volume":"1","author":"Yoo","year":"2010","journal-title":"Osong Public Heal. Res. Perspect."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Xu, D., Jiang, B., Ketela, T., Lemieux, S., Veillette, K., Martel, N., Davison, J., Sillaots, S., Trosok, S., and Bachewich, C. (2007). Genome-Wide Fitness Test and Mechanism-of-Action Studies of Inhibitory Compounds in Candida albicans. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030092"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1093\/genetics\/163.4.1287","article-title":"Mode of selection and experimental evolution of antifungal drug resistance in Saccharomyces cerevisiae","volume":"163","author":"Anderson","year":"2003","journal-title":"Genetics"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1080\/13693780500138971","article-title":"An update on antifungal targets and mechanisms of resistance inCandidaalbicans","volume":"43","author":"Akins","year":"2005","journal-title":"Med Mycol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1128\/EC.3.6.1391-1397.2004","article-title":"Role of Candida albicans Transcription Factor Upc2p in Drug Resistance and Sterol Metabolism","volume":"3","author":"Silver","year":"2004","journal-title":"Eukaryot. Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"6129","DOI":"10.1038\/ncomms7129","article-title":"Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2","volume":"6","author":"Yang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1099\/mic.0.2008\/017475-0","article-title":"Candida albicans UPC2 is transcriptionally induced in response to antifungal drugs and anaerobicity through Upc2p-dependent and -independent mechanisms","volume":"154","author":"Hoot","year":"2008","journal-title":"Microbiology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7375","DOI":"10.1128\/MCB.25.16.7375-7385.2005","article-title":"Dual Activators of the Sterol Biosynthetic Pathway of Saccharomyces cerevisiae: Similar Activation\/Regulatory Domains but Different Response Mechanisms","volume":"25","author":"Davies","year":"2005","journal-title":"Mol. Cell. Boil."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1128\/AAC.00995-10","article-title":"An A643V Amino Acid Substitution in Upc2p Contributes to Azole Resistance in Well-Characterized Clinical Isolates ofCandida albicans","volume":"55","author":"Hoot","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1128\/AAC.01102-09","article-title":"An A643T Mutation in the Transcription Factor Upc2p Causes Constitutive ERG11 Upregulation and Increased Fluconazole Resistance in Candida albicans","volume":"54","author":"Heilmann","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/j.1365-2443.2010.01470.x","article-title":"Transcription factors CgUPC2A and CgUPC2B regulate ergosterol biosynthetic genes in Candida glabrata","volume":"16","author":"Nagi","year":"2010","journal-title":"Genes Cells"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1128\/EC.00345-12","article-title":"Comparison of Sterol Import under Aerobic and Anaerobic Conditions in Three Fungal Species, Candida albicans, Candida glabrata, and Saccharomyces cerevisiae","volume":"12","author":"Zavrel","year":"2013","journal-title":"Eukaryot. Cell"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"R77","DOI":"10.1186\/gb-2010-11-7-r77","article-title":"Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering","volume":"11","author":"Kuo","year":"2010","journal-title":"Genome Boil."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"32466","DOI":"10.1074\/jbc.M204707200","article-title":"Transcriptional Profiling Identifies Two Members of the ATP-binding Cassette Transporter Superfamily Required for Sterol Uptake in Yeast","volume":"277","author":"Wilcox","year":"2002","journal-title":"J. Boil. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1093\/jac\/dkm321","article-title":"The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum","volume":"60","author":"Nakayama","year":"2007","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1128\/jb.163.1.199-207.1985","article-title":"Involvement of heme biosynthesis in control of sterol uptake by Saccharomyces cerevisiae","volume":"163","author":"Taylor","year":"1985","journal-title":"J. Bacteriol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1128\/JB.180.16.4177-4183.1998","article-title":"A Mutation in a Purported Regulatory Gene Affects Control of Sterol Uptake in Saccharomyces cerevisiae","volume":"180","author":"Crowley","year":"1998","journal-title":"J. Bacteriol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1128\/JB.180.7.1913-1919.1998","article-title":"Sterol Uptake in Saccharomyces cerevisiae Heme Auxotrophic Mutants is Affected by Ergosterol and Oleate but Not by Palmitoleate or by Sterol Esterification","volume":"180","author":"Ness","year":"1998","journal-title":"J. Bacteriol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"00662","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_103","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_104","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_105","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1128\/JB.181.13.4041-4049.1999","article-title":"Specific Chromosome Alterations in Fluconazole-Resistant Mutants of Candida albicans","volume":"181","author":"Perepnikhatka","year":"1999","journal-title":"J. Bacteriol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1093\/mmy\/myv002","article-title":"Trisomy of chromosome R confers resistance to triazoles in Candida albicans","volume":"53","author":"Li","year":"2015","journal-title":"Med. Mycol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.1073\/pnas.0809793106","article-title":"Formation of new chromosomes as a virulence mechanism in yeastCandida glabrata","volume":"106","author":"Blume","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1128\/AAC.41.10.2229","article-title":"Molecular biological characterization of an azole-resistant Candida glabrata isolate","volume":"41","author":"Marichal","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Mansfield, B.E., Oltean, H.N., Oliver, B.G., Hoot, S.J., Leyde, S.E., Hedstrom, L., and White, T.C. (2010). Azole Drugs Are Imported By Facilitated Diffusion in Candida albicans and Other Pathogenic Fungi. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001126"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/713687","article-title":"Antifungal Resistance and New Strategies to Control Fungal Infections","volume":"2012","author":"Vandeputte","year":"2011","journal-title":"Int. J. Microbiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1128\/AAC.00067-07","article-title":"Acquired Echinocandin Resistance in a Candida krusei Isolate Due to Modification of Glucan Synthase","volume":"51","author":"Kahn","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.fgb.2009.09.003","article-title":"Fungal echinocandin resistance","volume":"2","author":"Walker","year":"2010","journal-title":"Fungal Genet. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"6304","DOI":"10.1128\/AAC.00813-12","article-title":"Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance","volume":"56","author":"Katiyar","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e01692-18","DOI":"10.1128\/AAC.01692-18","article-title":"Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata","volume":"63","author":"Shields","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Tsai, H.-J., and Nelliat, A. (2019). A Double-Edged Sword: Aneuploidy is a Prevalent Strategy in Fungal Adaptation. Genes, 10.","DOI":"10.3390\/genes10100787"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"4377","DOI":"10.1128\/AAC.48.11.4377-4386.2004","article-title":"Molecular Mechanisms of Primary Resistance to Flucytosine in Candida albicans","volume":"48","author":"Hope","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1128\/AAC.49.8.3101-3108.2005","article-title":"Inactivation of the FCY2 Gene Encoding Purine-Cytosine Permease Promotes Cross-Resistance to Flucytosine and Fluconazole in Candida lusitaniae","volume":"49","author":"Bouchoux","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_118","first-page":"1360","article-title":"Acquisition of Flucytosine, Azole, and Caspofungin Resistance in Candida glabrata Bloodstream Isolates Serially Obtained from a Hematopoietic Stem Cell Transplant Recipient","volume":"54","author":"Hennequin","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"S445","DOI":"10.1093\/infdis\/jix131","article-title":"Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment","volume":"216","author":"Arendrup","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_120","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"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/9\/6\/312\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:37:01Z","timestamp":1760175421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/9\/6\/312"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,9]]},"references-count":120,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["antibiotics9060312"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics9060312","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,9]]}}}