Abrogation of Triazole Resistance upon Deletion of CDR1 in a Clinical Isolate of Candida auris
Open accessAbstract
Candida auris has rapidly emerged as a health care-associated and multidrug-resistant pathogen of global concern. In this work, we examined the relative expression of the four C. auris genes with the highest degree of homology to Candida albicans CDR1 and MDR1 among three triazole-resistant clinical isolates as compared to the triazole-susceptible genome reference clinical isolate.
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U.S. isolates are closely related to those of South America and South Asia.
“Because U.S. isolates are closely related to those of South America and South Asia, we used the genome sequenced South Asian clade CA 0387 (B8441) to compare with C. albicans (4, 30 – 32).”
From Differential skin immune responses in mice intradermally infected with <i>Candida auris</i> and <i>Candida albicans</i> (2023) · cites this paper as [30]
The Results and Discussion identify AR0387 (B8441) as a South Asian-clade isolate, but do not address whether U.S. isolates are closely related to isolates from South America or South Asia. Searches for U.S. isolates and phylogenetic relatedness found no passage establishing that relationship. (LLM, conf=0.76)
Experimental — accuracy not yet measuredCandida species known for hyperactive ABC-transporters, such as C. glabrata and C. auris, displayed significantly reduced susceptibility to pitavastatin compared to wild-type C. albicans.
“Moreover, Candida species that are known for their hyperactive ABC-transporters such as C. glabrata and C. auris displayed significantly reduced susceptibility to pitavastatin as compared to the wild type C. albicans strain48–50.”
From Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species (2020) · cites this paper as [48]
Correction of the TAC1B A640V mutation to wild type in AR0390 confers susceptibility to fluconazole with an MIC of 16 mg/L.
“Correction of this mutation to the wild type sequence in clinical isolate AR0390 likewise confers susceptibility to fluconazole with an MIC of 16 mg/L.”
From Delineation of the Direct Contribution of Candida auris <i>ERG11</i> Mutations to Clinical Triazole Resistance (2021) · cites this paper as [16]
AR0390 carries a mutation encoding the A640V substitution in the transcription factor Tac1B which likely leads to overexpression of the Cdr1 drug efflux transporter.
“AR0390 also carries a mutation (encoding the A640V substitution) in the gene encoding the transcription factor Tac1B which likely leads to overexpression of the Cdr1 drug efflux transporter (15, 16).”
From Delineation of the Direct Contribution of Candida auris <i>ERG11</i> Mutations to Clinical Triazole Resistance (2021) · cites this paper as [16]
Transformants were confirmed by Sanger sequencing to possess each of the four ERG11 alleles of interest.
“transformations were performed by electroporation to generate transformants which were confirmed by Sanger sequencing to possess each of the four ERG11 alleles of interest as previously described (15, 16).”
From Delineation of the Direct Contribution of Candida auris <i>ERG11</i> Mutations to Clinical Triazole Resistance (2021) · cites this paper as [16]
Increased expression of the Candida auris ABC-type efflux pump-encoding gene CDR1 has previously been shown to substantially contribute to clinical triazole resistance.
“the increased expression of the C. auris ABC-type efflux pump-encoding gene CDR1 has previously been shown to substantially contribute to clinical triazole resistance (20, 21).”
From Mutations in <i>TAC1B</i> : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris (2020) · cites this paper as [20]
The level of CDR1 expression in the evolved strains is similar to that previously described among extensively fluconazole-resistant Candida auris clinical isolates.
“This level of CDR1 expression is similar to that previously described among extensively fluconazole-resistant C. auris clinical isolates (20).”
From Mutations in <i>TAC1B</i> : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris (2020) · cites this paper as [20]
The degree of CDR1 overexpression observed among fluconazole-evolved strains was similar to that previously reported among fluconazole-resistant clinical C. auris isolates.
“the degree of CDR1 overexpression observed among fluconazole-evolved strains was similar to that previously reported among fluconazole-resistant clinical C. auris isolates (20)”
From Mutations in <i>TAC1B</i> : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris (2020) · cites this paper as [20]
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- Authors
- Rybak, J. M., Doorley, L. A., Nishimoto, A. T., Barker, K. S., Palmer, G. E., & Rogers, P. D.
- Affiliations
- University of Tennessee Health Science Center (US)
- ORCID
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2019-04
- Volume
- 63
- Issue
- 4
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC6437491
- OpenAlex
- W2913720564
- Cited by
- 141
- References
- 14
- Citations by year
- 2026: 11 · 2025: 30 · 2024: 12 · 2023: 20 · 2022: 18 · 2021: 22 · 2020: 20 · 2019: 8
- FWCI
- 13.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01 A1058145)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Candida auris, triazole resistance, CDR1, multidrug resistance, gene deletion, clinical isolates, antifungal resistance, multidrug resistance genes
- MeSH terms
- Microorganisms, Genetically-Modified, CRISPR-Associated Protein 9, Antifungal Agents, Candida, Candidiasis, Fungal Proteins, Humans, Microbial Sensitivity Tests, Triazoles, Fluconazole, Gene Expression Regulation, Fungal, Gene Deletion, ATP Binding Cassette Transporter, Subfamily B, Member 1, Drug Resistance, Fungal, Membrane Transport Proteins
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