Abc1p Is a Multidrug Efflux Transporter That Tips the Balance in Favor of Innate Azole Resistance in Candida krusei

Lamping, Erwin; Ranchod, Amrita; Nakamura, Kenjirou; Tyndall, Joel D. A.; Niimi, Kyoko; Holmes, Ann R.; Niimi, Masakazu; Cannon, Richard D.

doi:10.1128/aac.01095-08

Cited by 100Antifungal resistance and susceptibilityFungal and yeast genetics researchDrug Transport and Resistance Mechanisms

Abc1p Is a Multidrug Efflux Transporter That Tips the Balance in Favor of Innate Azole Resistance in Candida krusei

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Lamping, Erwin, Ranchod, Amrita, Nakamura, Kenjirou, Tyndall, Joel D. A., Niimi, Kyoko, Holmes, Ann R., Niimi, Masakazu, Cannon, Richard D.·2009·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.01095-08PMC PMC2630665

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Abstract

Most Candida krusei strains are innately resistant to fluconazole (FLC) and can cause breakthrough candidemia in immunocompromised individuals receiving long-term prophylactic FLC treatment. Although the azole drug target, Erg11p, of C. krusei has a relatively low affinity for FLC, drug efflux pumps are also believed to be involved in its innate FLC resistance. We describe here the isolation and characterization of Abc1p, a constitutively expressed multidrug efflux pump, and investigate ERG11 and ABC1 expression in C. krusei. Examination of the ERG11 promoter revealed a conserved azole responsive element that has been shown to be necessary for the transcription factor Upc2p mediated upregulation by azoles in related yeast. Extensive cloning and sequencing identified three distinct ERG11 alleles in one of two C. krusei strains. Functional overexpression of ERG11 and ABC1 in Saccharomyces cerevisiae conferred high levels of resistance to azoles and a range of unrelated Abc1p pump substrates, while small molecule inhibitors of Abc1p chemosensitized C. krusei to azole antifungals. Our data show that despite the presence of multiple alleles of ERG11 in some, likely aneuploid, C. krusei strains, it is mainly the low affinity of Erg11p for FLC, together with the constitutive but low level of expression of the multidrug efflux pump Abc1p, that are responsible for the innate FLC resistance of C. krusei.

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Overexpression of ERG11 and the ABC transporter ABC1 has also been related to fluconazole resistance in C. krusei.
“However, overexpression of ERG11 [93] and the ABC transporter, ABC1, has also been related to fluconazole resistance in this species [94].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [94]
Other transporter genes are upregulated in azole-resistant C. glabrata, C. dubliniensis, C. krusei, and C. tropicalis.
“Other transporter genes have been reported to be upregulated in azole-resistant C. glabrata (CgCDR1, CgCDR2 (formerly named PDH1) and CgSNQ2 (another ABC transporter)) [100–102], C. dubliniensis (CdCDR1 and CdCDR2) [103], C. krusei (ABC1 and 2) [104, 105], and C. tropicalis (CDR1-homologue) isolates [44].”
From CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [104]

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Fakhim, H., Emami, S., Vaezi, A., Hashemi, S. M., Faeli, L., Diba, K., Dannaoui, É., & Badali, H. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01106-16 · Cited by 29 · see citing works
Fluconazole treatment of Candidal infections caused by non-Albicans Candida species
Wout, J. W. V. ’. (1996) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/bf01591361 · Cited by 54 · see citing works

Authors: Lamping, E., Ranchod, A., Nakamura, K., Tyndall, J. D. A., Niimi, K., Holmes, A. R., Niimi, M., & Cannon, R. D.
Affiliations: University of Otago (NZ)
Nippon Dental University (JP)
National Institute of Infectious Diseases (JP)
Corresponding author: Lamping, Erwin
ORCID: Lamping, Erwin
Tyndall, Joel D. A.
Holmes, Ann R.
Cannon, Richard D.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2009-02
Volume: 53
Issue: 2
Pages: 354-369
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.01095-08
PMC: PMC2630665
OpenAlex: W2128394219
Cited by: 100
References: 57
Citations by year: 2026: 2 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 8 · 2020: 13 · 2019: 5 · 2018: 8 · 2017: 10 · 2016: 6 · 2015: 2 · 2014: 7 · 2013: 2 · 2012: 2
FWCI: 4.50
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)
PubMed (publishedVersion)
Funders: International Association for Dental Research
National Institute of Dental and Craniofacial Research (R21DE015075-RDC, R21DE015075, R01DE016885-01-RDC, R01DE016885)
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 krusei, multidrug efflux pumps, azole resistance, fluconazole, ERG11, antifungal resistance, chemosensitization, Saccharomyces cerevisiae complementation, aneuploidy
MeSH terms: Amino Acid Sequence, Animals, Antifungal Agents, Azoles, Candida, Candidiasis, Cell Membrane, Endoplasmic Reticulum, Humans, Phenotype, Plasmids, Saccharomyces cerevisiae, Blotting, Southern, Blotting, Northern, Chromosomes, Fungal, ATP-Binding Cassette Transporters, Reverse Transcriptase Polymerase Chain Reaction, Drug Resistance, Fungal

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Abc1p Is a Multidrug Efflux Transporter That Tips the Balance in Favor of Innate Azole Resistance in Candida krusei

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