Cited by 815Antifungal resistance and susceptibilityDrug Transport and Resistance MechanismsFungal and yeast genetics research

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Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters

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Sanglard, D, Kuchler, K, Ischer, F, Pagani, J L, Monod, M, Bille, J·1995·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.39.11.2378PMC PMC162951

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Abstract

Azole antifungal agents, and especially fluconazole, have been used widely to treat oropharyngeal candidiasis in patients with AIDS. An increasing number of cases of clinical resistance against fluconazole, often correlating with in vitro resistance, have been reported. To investigate the mechanisms of resistance toward azole antifungal agents at the molecular level in clinical C. albicans isolates, we focused on resistance mechanisms related to the cellular target of azoles, i.e., cytochrome P450(14DM) (14DM) and those regulating the transport or accumulation of fluconazole. The analysis of sequential isogenic C. albicans isolates with increasing levels of resistance to fluconazole from five AIDS patients showed that overexpression of the gene encoding 14DM either by gene amplification or by gene deregulation was not the major cause of resistance among these clinical isolates. We found, however, that fluconazole-resistant C. albicans isolates failed to accumulate 3H-labelled fluconazole. This phenomenon was reversed in resistant cells by inhibiting the cellular energy supply with azide, suggesting that resistance could be mediated by energy-requiring efflux pumps such as those described as ATP-binding cassette (ABC) multidrug transporters. In fact, some but not all fluconazole-resistant clinical C. albicans isolates exhibited up to a 10-fold relative increase in mRNA levels for a recently cloned ABC transporter gene called CDR1. In an azole-resistant C. albicans isolate not overexpressing CDR1, the gene for another efflux pump named BENr was massively overexpressed. This gene was cloned from C. albicans for conferring benomyl resistance in Saccharomyces cerevisiae. Therefore, at least the overexpression or the deregulation of these two genes potentially mediates resistance to azoles in C. albicans clinical isolates from AIDS patients with oropharyngeal candidiasis. Involvement of ABC transporters in azole resistance was further evidenced with S. cerevisiae mutants lacking specific multidrug transporters which were rendered hypersusceptible to azole derivatives including fluconazole, itraconazole, and ketoconazole.

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Authors: Sanglard, D., Kuchler, K., Ischer, F., Pagani, J. L., Monod, M., & Bille, J.
Affiliations: Centre Hospitalier Universitaire Vaudois (CH)
Institut de Microbiologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
ORCID: Sanglard, D
Kuchler, K
Pagani, J L
Monod, M
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 1995-11
Volume: 39
Issue: 11
Pages: 2378-2386
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.39.11.2378
PMC: PMC162951
OpenAlex: W2115130703
Cited by: 815
References: 48
Citations by year: 2026: 10 · 2025: 19 · 2024: 13 · 2023: 12 · 2022: 11 · 2021: 20 · 2020: 15 · 2019: 25 · 2018: 24 · 2017: 32 · 2016: 24 · 2015: 27 · 2014: 26 · 2013: 26 · 2012: 22
FWCI: 32.03
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Funders: Bundesamt für Gesundheit
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: Candida albicans, azole resistance, fluconazole resistance, multidrug transporter, ABC transporters, CDR1, efflux pumps, oropharyngeal candidiasis, AIDS patients, drug accumulation, gene overexpression, benomyl resistance
MeSH terms: Antifungal Agents, Azoles, Base Sequence, Candida albicans, Candidiasis, Oral, DNA, Fungal, Drug Resistance, Microbial, Fungal Proteins, Genes, Fungal, Humans, Microbial Sensitivity Tests, Molecular Sequence Data, Nucleic Acid Hybridization, Plasmids, RNA, Fungal, Saccharomyces cerevisiae, Blotting, Northern, Fluconazole, Polymerase Chain Reaction, AIDS-Related Opportunistic Infections, Drug Resistance, Multiple, ATP-Binding Cassette Transporters, ATP Binding Cassette Transporter, Subfamily B, Member 1, Membrane Transport Proteins

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Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters

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