Distinct Patterns of Gene Expression Associated with Development of Fluconazole Resistance in Serial Candida albicans Isolates from Human Immunodeficiency Virus-Infected Patients with Oropharyngeal Candidiasis

Lopez-Ribot, Jose L.; McAtee, Robert K.; Lee, Linda N.; Kirkpatrick, William R.; White, Theodore C.; Sanglard, Dominique; Patterson, Thomas F.

doi:10.1128/aac.42.11.2932

Cited by 210Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Distinct Patterns of Gene Expression Associated with Development of Fluconazole Resistance in Serial Candida albicans Isolates from Human Immunodeficiency Virus-Infected Patients with Oropharyngeal Candidiasis

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Lopez-Ribot, Jose L., McAtee, Robert K., Lee, Linda N., Kirkpatrick, William R., White, Theodore C., Sanglard, Dominique, Patterson, Thomas F.·1998·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.42.11.2932PMC PMC105968

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Abstract

Resistance to fluconazole is becoming an increasing problem in the management of oropharyngeal candidiasis in human immunodeficiency virus-infected patients. Strains obtained from five patients developed decreased fluconazole susceptibility over time. DNA strain typing confirmed the high degree of relatedness among isolates from one patient and the variability among isolates from different patients. Expression of genes involved in development of fluconazole resistance was monitored in each isolate using probes specific for ERG11 (lanosterol 14α-demethylase), MDR1 (a major facilitator), and CDR (ATP-binding cassette or ABC transporter) genes. Increased expression of CDR genes was detected in the series of isolates from two patients. Isolates from one of the two patients also demonstrated increased ERG11 expression, whereas isolates from the other patient did not. Increased levels of MDR1 mRNA correlated with increased resistance in sequential isolates from another patient. Initial overexpression of MDR1 with subsequent overexpression of CDR genes and a final isolate again overexpressing MDR1 were detected in serial isolates from another patient. In another patient, overexpression of these genes was not detected despite an eightfold increase in fluconazole MIC. In this patient, sequence data of the ERG11 gene revealed no point mutations associated with decreased susceptibility. Five different patterns of gene expression were observed in isolates recovered from five patients who developed resistance. Therefore, these experiments demonstrate that a variety of mechanisms or combinations of mechanisms are associated with the development of fluconazole drug resistance. Additional studies are needed to estimate the frequency and clinical impact of these mechanisms of resistance.

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Overexpression of the efflux transporter genes CDR1, CDR2, and MDR1 is a common mechanism of drug resistance in C. albicans.
“Overexpression of the efflux transporter genes CDR1 , CDR2 , and MDR1 is a common mechanism of drug resistance in this organism (10, 17, 26).”
From Gain-of-Function Mutations in UPC2 Are a Frequent Cause of ERG11 Upregulation in Azole-Resistant Clinical Isolates of Candida albicans (2012) · cites this paper as [17]

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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
White, T. C. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.7.1482 · Cited by 612 · see citing works
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Authors: Lopez-Ribot, J. L., McAtee, R. K., Lee, L. N., Kirkpatrick, W. R., White, T. C., Sanglard, D., & Patterson, T. F.
Affiliations: The University of Texas at San Antonio Health Science Center (US)
Center for Infectious Disease Research (US)
Centre Hospitalier Universitaire Vaudois (CH)
ORCID: Lopez-Ribot, Jose L.
Lee, Linda N.
White, Theodore C.
Sanglard, Dominique
Patterson, Thomas F.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 1998-11
Volume: 42
Issue: 11
Pages: 2932-2937
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.42.11.2932
PMC: PMC105968
OpenAlex: W1832945357
Cited by: 210
References: 1
Citations by year: 2026: 3 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 7 · 2018: 8 · 2017: 12 · 2016: 5 · 2015: 7 · 2014: 10 · 2013: 3 · 2012: 10
FWCI: 5.79
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
PubMed Central (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed (publishedVersion)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Funders: Pfizer
University of Texas Health Science Center at San Antonio
National Institute of Allergy and Infectious Diseases (R29AI042401)
National Institute of Dental and Craniofacial Research (R01DE011381)
National Center for Research Resources (M01RR001346)
NIH Clinical Center
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords: fluconazole resistance, Candida albicans, oropharyngeal candidiasis, HIV infection, drug resistance mechanisms, gene expression, ERG11, MDR1, ABC transporters, serial isolates, antifungal susceptibility
MeSH terms: Antifungal Agents, Candida albicans, Candidiasis, Oral, DNA-Binding Proteins, Drug Resistance, Microbial, Fungal Proteins, Humans, Pharyngeal Diseases, RNA, Messenger, HIV Infections, Fluconazole, Gene Expression Regulation, Fungal, ATP Binding Cassette Transporter, Subfamily B, Member 1, Membrane Transport Proteins

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Distinct Patterns of Gene Expression Associated with Development of Fluconazole Resistance in Serial Candida albicans Isolates from Human Immunodeficiency Virus-Infected Patients with Oropharyngeal Candidiasis

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