Function of Candida glabrata ABC transporter gene, PDH1
Abstract
The rapid increase in azole resistance during treatment of patients infected with Candida glabrata may be due to increased azole efflux mediated by ABC transporters, as occurs with increased expression of PDR5 in Saccharomyces cerevisiae. Two known C. glabrata homologues of PDR5 influencing azole susceptibility are PDH1 (CgCDR2) and CgCDR1. Disruption of PDH1 in a cgcdr1::ura3 strain increased susceptibility to rhodamine 6G, cycloheximide and chloramphenicol, and also increased rhodamine 6G accumulation, all properties of pdr5 null mutants. Overexpression of PDH1 in S. cerevisiae complemented the pdr5 mutation by reversing susceptibility to rhodamine 6G, chloramphenicol and cycloheximide, as well as by decreasing rhodamine 6G intracellular concentration. Expression of PDH1 in a C. glabrata cgcdr1::ura3 pdh1Δ::ura3 mutant using a multicopy plasmid almost completely restored the wild‐type phenotype, showing that PDH1 at higher levels of expression can replace CgCDR1. Because PDH1 and CgCDR1 have both been reported to have upstream sequences similar to the Pdr1p‐ and Pdr3p‐binding elements of PDR5, we sought similarities in regulation between the three genes. Abundance of PDH1 and CgCDR1 mRNA in C. glabrata was increased by rhodamine 6G, cycloheximide and oligomycin, properties in common with PDR5. PDH1, CgCDR1 and PDR5 have striking similarities in function and regulation. Published in 2003 by John Wiley & Sons, Ltd.
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Candida 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 [50]
The PKC-mediated cell wall integrity pathway is required for the transcriptional activation of multidrug efflux pumps, the most frequent azole resistance mechanism in clinical settings worldwide.
“The PKC-mediated cell wall integrity pathway has been shown to be required for the transcriptional activation of multidrug efflux pumps, which is the most frequent azole resistance mechanism in clinical settings world-wide [91,101,104,105].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [105]
CgCDR1, CgCDR2, CgSNQ2, CgPDR1 and CgERG11 code for plasma membrane ABC transporters, a zinc finger transcriptional regulator of pleiotropic drug resistance genes, and lanosterol 14-α-demethylase (target of fluconazole), respectively.
“These five genes, CgCDR1, CgCDR2, and CgSNQ2, CgPDR1 and CgERG11, code for plasma membrane ATP-binding cassette transporters, zinc finger transcriptional regulator of pleiotropic drug resistance genes, and lanosterol 14-␣-demethylase (target of fluconazole), respectively (7,9,11,12).”
From The Rho1 GTPase-activating protein CgBem2 is required for survival of azole stress in Candida glabrata (2011) · cites this paper as [9]
Drug efflux is the most frequent mechanism of acquired fluconazole resistance, and is mediated by transmembrane transporter molecules of either the ATP-binding cassette or major facilitator superfamilies.
“Drug efflux is the most frequent mechanism, and is mediated by transmembrane transporter molecules of either the ATP-binding cassette (ABC) or major facilitator (MFS) superfamilies [48,49].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [48]
C. glabrata readily develops cross-resistance to azoles, including fluconazole, itraconazole, voriconazole and posaconazole, which is often associated with upregulation of ABC transporters CDR1 and SNQ2.
“C. glabrata readily develops cross-resistance to azoles, including fluconazole, itraconazole, voriconazole and posaconazole, which is often associated with upregulation of ATP-binding cassette (ABC) transporters, such as CDR1 and SNQ2, that effectively pump the drugs out of the yeast cell”
From Genetic Drivers of Multidrug Resistance in Candida glabrata (2016) · cites this paper as Izumikawa et al., 2003
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References 31 · Cited by 67
- Authors
- Izumikawa, K., Kakeya, H., Tsai, H., Grimberg, B., & Bennett, J. E.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Bennett, John E.
- Venue
- Yeast
- Publisher
- Wiley
- Published
- 2003-01-07
- Volume
- 20
- Issue
- 3
- Pages
- 249-261
- ISSN
- 0749-503X (ISSN-L)
- 1097-0061
- OpenAlex
- W2099913954
- Cited by
- 67
- References
- 31
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 6 · 2015: 1 · 2014: 6 · 2013: 5 · 2012: 2
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Yeast (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- Candida glabrata, ABC transporters, azole resistance, PDR5, drug efflux, gene expression regulation, Pdr1p, transcriptional activation, rhodamine 6G, cycloheximide, chloramphenicol, oligomycin, multidrug resistance
- MeSH terms
- Antifungal Agents, Chloramphenicol, Cycloheximide, DNA, Fungal, Fungal Proteins, Immunodiffusion, Humans, Membrane Proteins, Protein Synthesis Inhibitors, Rhodamines, RNA, Fungal, Transformation, Genetic, Blotting, Northern, Gene Expression Regulation, Fungal, Polymerase Chain Reaction, Mutagenesis, Insertional, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins, Candida glabrata
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