Cited by 43Antifungal resistance and susceptibilityDrug Transport and Resistance MechanismsFungal and yeast genetics research

Clotrimazole Drug Resistance in Candida glabrata Clinical Isolates Correlates with Increased Expression of the Drug: H+ Antiporters CgAqr1, CgTpo1_1, CgTpo3, and CgQdr2

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Costa, Catarina, Ribeiro, Jonathan, Miranda, Isabel M., Silva-Dias, Ana, Cavalheiro, Mafalda, Costa-de-Oliveira, Sofia, Rodrigues, Acácio G., Teixeira, Miguel C.·2016·Frontiers in Microbiology

Abstract

For years, antifungal drug resistance in Candida species has been associated to the expression of ATP-Binding Cassette (ABC) multidrug transporters. More recently, a few drug efflux pumps from the Drug:H(+) Antiporter (DHA) family have also been shown to play a role in this process, although to date only the Candida albicans Mdr1 transporter has been demonstrated to be relevant in the clinical acquisition of antifungal drug resistance. This work provides evidence to suggest the involvement of the C. glabrata DHA transporters CgAqr1, CgQdr2, CgTpo1_1, and CgTpo3 in the clinical acquisition of clotrimazole drug resistance. A screening for azole drug resistance in 138 C. glabrata clinical isolates, from patients attending two major Hospitals in Portugal, was performed. Based on this screening, 10 clotrimazole susceptible and 10 clotrimazole resistant isolates were selected for further analysis. The transcript levels of CgAQR1, CgQDR2, CgTPO1_1, and CgTPO3 were found to be significantly up-regulated in resistant isolates when compared to the susceptible ones, with a level of correlation that was found to be similar to that of CgCDR2, an ABC gene known to be involved in the clinical acquisition of resistance. As a proof-of-concept experiment, the CgTPO3 gene was deleted in an azole resistant C. glabrata isolate, exhibiting high levels of expression of this gene. The deletion of CgTPO3 in this isolate was found to lead to decreased resistance to clotrimazole and fluconazole, and increased accumulation of azole drugs, thus suggesting the involvement of this transporter in the manifestation of azole resistance.

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Crossref · 10.3389/fmicb.2016.00526

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  • Another possible resistance mechanism in C. glabrata may involve the major facilitator superfamily transporter TPO3, as its depletion results in increased sensitivity to fluconazole and clotrimazole.

    “Another possible resistance mechanism in C. glabrata may involve the major facilitator superfamily (MFS) transporter, TPO3, as its depletion results in increased sensitivity to fluconazole and clotrimazole [100].”

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Authors
Costa, C., Ribeiro, J., Miranda, I. M., Silva-Dias, A., Cavalheiro, M., Costa-de-Oliveira, S., Rodrigues, A. G., & Teixeira, M. C.
Affiliations
  • University of Lisbon (PT)
  • Universidade do Porto (PT)
Corresponding author
Teixeira, Miguel C.
Venue
Frontiers in Microbiology
Published
2016-04-19
Volume
7
Pages
526-526
ISSN
1664-302X (ISSN-L)
OpenAlex
W2338841684
Cited by
43
References
46
Citations by year
2026: 4 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 2
FWCI
4.31
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Microbiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Fundação para a Ciência e a Tecnologia (“PTDC/EBB-BIO/119356/2010, PTDC/BBB-BIO/4004/2014, UID/BIO/04565/2013, SFRH/BPD/100863/2014”)
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 glabrata, clotrimazole resistance, azole resistance, gene expression, gene deletion, fluconazole, clinical isolates

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