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Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters
Open accessAbstract
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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In the citing paper
“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 [26]
Experimental — accuracy not yet measuredIn the citing paper
“For C. albicans, upregulation of the ATP-binding cassette (ABC) transporters, Cdr1 and Cdr2 (Candida drug resistance 1 and 2), and major facilitator transporter Mdr1 (multidrug resistance 1) have been implicated in azole resistance50,51.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [50]
In the citing paper
“In two separate studies, it was found that isolates of C. albicans taken from HIV-infected individuals had increased mRNA levels of CDR1, which has been shown to confer resistance to the azole antifungals.77–79”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans (2020) · cites this paper as [77]
In the citing paper
“The ATP-binding cassette (ABC) transporters Cdr1 and Cdr2 have both been well documented as drivers of azole resistance and were first implicated in clinical azole resistance in isolates in HIV-infected patients with oropharyngeal candidiasis.75–77”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans (2020) · cites this paper as [77]
In the citing paper
“Overexpression of the ATP binding cassette (ABC) transporters Cdr1 and Cdr2 results in the efflux of all azole antifungals”
From Multidrug transporters and alterations in sterol biosynthesis contribute to azole antifungal resistance in Candida parapsilosis (2015) · cites this paper as [12]
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Metadata
- 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.
- 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
- 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
- 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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