Increased expression and hotspot mutations of the multidrug efflux transporter, CDR1 in azole-resistant Candida albicans isolates from vaginitis patients

Looi, Chung Yeng; d'Silva, Emily Christine; Seow, Heng Fong; Rosli, Rozita; Ng, Kee Peng; Chong, Pei Pei

doi:10.1016/j.femsle.2005.06.036

Cited by 20Antifungal resistance and susceptibilityDrug Transport and Resistance MechanismsAntibiotic Resistance in Bacteria

Increased expression and hotspot mutations of the multidrug efflux transporter, CDR1 in azole-resistant Candida albicans isolates from vaginitis patients

Looi, Chung Yeng, d'Silva, Emily Christine, Seow, Heng Fong, Rosli, Rozita, Ng, Kee Peng, Chong, Pei Pei·2005·FEMS Microbiology Letters

DOI 10.1016/j.femsle.2005.06.036

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Abstract

The aims of our research were to investigate the gene expression of the multidrug efflux transporter, CDR1 and the major drug facilitator superfamily transporter, MDR1 gene in azole drug-resistant Candida albicans and Candida glabrata clinical isolates recovered from vaginitis patients; and to identify hotspot mutations that may be present in the C. albicans CaCDR1 gene that could be associated with drug-resistance. The relative expression of the CDR1 and MDR1 transcripts in ketoconazole and clotrimazole-resistant isolates and drug-susceptible ATCC strains were determined by semi-quantitative reverse transcription-polymerase chain reaction. Expression of CaCDR1 transcript was upregulated to varying extents in all three azole-resistant C. albicans isolates studied (1.6-, 3.7- and 3.9-fold) and all three C. glabrata isolates tested (at 1.9-, 2.3- and 2.7-fold). The overexpression level of CaCDR1 in the isolates correlated with the degree of resistance as reflected by the minimum inhibitory concentration (MIC) of the drugs. The messenger RNA for another efflux pump, MDR1, was also overexpressed in one of the azole-resistant C. albicans isolates that overexpressed CDR1. This finding suggests that drug-resistance may involve synergy between energy-dependent drug efflux pumps CDR1p and MDR1p in some but not all isolates. Interestingly, DNA sequence analysis of the promoter region of the CaCDR1 gene revealed several point mutations in the resistant clinical isolates compared to the susceptible isolates at 39, 49 and 151 nucleotides upstream from the ATG start codon. This finding provides new information on point mutations in the promoter region which may be responsible for the overexpression of CDR1 in drug-resistant isolates.

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Alterations in the promoter region of the efflux pump CDR1 have already been reported in azole-resistant strains.
“Alterations in the promoter region of the efflux pump CDR1 have already been reported in azole-resistant strains,33,34”
From Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata (2021) · cites this paper as [34]

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Authors: Looi, C. Y., d'Silva, E. C., Seow, H. F., Rosli, R., Ng, K. P., & Chong, P. P.
Affiliations: Universiti Putra Malaysia (MY)
University of Malaya (MY)
Corresponding author: Chong, Pei Pei
ORCID: Looi, Chung Yeng
Seow, Heng Fong
Rosli, Rozita
Chong, Pei Pei
Venue: FEMS Microbiology Letters
Publisher: Oxford University Press (OUP)
Published: 2005-08
Volume: 249
Issue: 2
Pages: 283-289
ISSN: 0378-1097 (ISSN-L)
1574-6968
DOI: 10.1016/j.femsle.2005.06.036
OpenAlex: W2163829185
Cited by: 20
References: 22
Citations by year: 2024: 1 · 2022: 1 · 2021: 4 · 2019: 1 · 2018: 3 · 2016: 1 · 2013: 1
FWCI: 1.07
Type: journal article
Language: en
Open access: closed
Locations: FEMS Microbiology Letters (publishedVersion)
PubMed (publishedVersion)
Victoria University Research Repository (Victoria University) (submittedVersion)
Funders: Ministério da Ciência, Tecnologia e Inovação
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 Medicine › Antibiotic Resistance in Bacteria
Keywords: CDR1, MDR1, multidrug efflux pumps, Candida albicans, Candida glabrata, azole resistance, vaginal candidiasis, promoter mutations, gene overexpression, ketoconazole resistance, clotrimazole resistance, antifungal resistance
MeSH terms: Antifungal Agents, Base Sequence, Candida albicans, Candidiasis, Clotrimazole, Female, Fungal Proteins, Humans, Ketoconazole, Molecular Sequence Data, Promoter Regions, Genetic, Transcription, Genetic, Vaginitis, Gene Expression Regulation, Fungal, Point Mutation, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, Drug Resistance, Fungal, Membrane Transport Proteins, Candida glabrata

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Increased expression and hotspot mutations of the multidrug efflux transporter, CDR1 in azole-resistant Candida albicans isolates from vaginitis patients

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