The dual role of candida glabrata drug:H+ antiporter CgAqr1 (ORF CAGL0J09944g) in antifungal drug and acetic acid resistance.
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Opportunistic Candida species often have to cope with inhibitory concentrations of acetic acid, in the acidic environment of the vaginal mucosa. Given that the ability of these yeast species to tolerate stress induced by weak acids and antifungal drugs appears to be a key factor in their persistence and virulence, it is crucial to understand the underlying mechanisms. In this study, the drug:H(+) antiporter CgAqr1 (ORF CAGL0J09944g), from Candida glabrata, was identified as a determinant of resistance to acetic acid, and also to the antifungal agents flucytosine and, less significantly, clotrimazole. These antifungals were found to act synergistically with acetic acid against this pathogen. The action of CgAqr1 in this phenomenon was analyzed. Using a green fluorescent protein fusion, CgAqr1 was found to localize to the plasma membrane and to membrane vesicles when expressed in C. glabrata or, heterologously, in Saccharomyces cerevisiae. Given its ability to complement the susceptibility phenotype of its S. cerevisiae homolog, ScAqr1, CgAqr1 was proposed to play a similar role in mediating the extrusion of chemical compounds. Significantly, the expression of this gene was found to reduce the intracellular accumulation of (3)H-flucytosine and, to a moderate extent, of (3)H-clotrimazole, consistent with a direct role in antifungal drug efflux. Interestingly, no effect of CgAQR1 deletion could be found on the intracellular accumulation of (14)C-acetic acid, suggesting that its role in acetic acid resistance may be indirect, presumably through the transport of a still unidentified physiological substrate. Although neither of the tested chemicals induces changes in CgAQR1 expression, pre-exposure to flucytosine or clotrimazole was found to make C. glabrata cells more sensitive to acetic acid stress. Results from this study show that CgAqr1 is an antifungal drug resistance determinant and raise the hypothesis that it may play a role in C. glabrata persistent colonization and multidrug resistance.
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Acetic acid acted synergistically with clotrimazole and flucytosine in C. glabrata.
“Another study reported that acetic acid, other alternative carbon source, acted synergistically with clotrimazole and flucytosine in C. glabrata (Costa et al., 2013).”
From Candida glabrata susceptibility to antifungals and phagocytosis is modulated by acetate (2015) · cites this paper as Costa et al., 2013
Aqr1 was suggested to play a role in intermediating the extrusion of chemical compounds, dropping the intracellular accumulation of 3H-flucytosine and, to a minor degree, of 3H-clotrimazole.
“Aqr1 (located in plasma membrane and in the membrane vesicles) was suggested to play a role in intermediating the extrusion of chemical compounds, dropping the intracellular accumulation of 3H-flucytosine and, in a minor degree, of 3H-clotrimazole, which is reliable with a direct role in antifungal drug efflux.”
From Candida glabrata Biofilms: How Far Have We Come? (2017) · cites this paper as [209]
Aqr1 is an antifungal drug resistance determinant and may play an essential part in C. glabrata persistent colonization and multidrug resistance.
“Therefore, Costa et al. [209] showed that Aqr1 is an antifungal drug resistance determinant and it may play an essential part in C. glabrata persistent colonization and multidrug resistance.”
From Candida glabrata Biofilms: How Far Have We Come? (2017) · cites this paper as [209]
AQR1 deletion had no effect on the intracellular accumulation of 14C-acetic acid, suggesting that its role in acetic acid resistance may be indirect.
“When an AQR1 deletion was performed, no effect could be noticed on the intracellular accumulation of 14C-acetic acid, thus suggesting that its role in acetic acid resistance may be indirect, possibly through the transport of a so far undisclosed physiological substrate.”
From Candida glabrata Biofilms: How Far Have We Come? (2017) · cites this paper as [209]
Pre-exposure to flucytosine or clotrimazole makes C. glabrata cells more tolerant to acetic acid stress.
“The pre-exposure to flucytosine or clotrimazole was found to make C. glabrata cells more tolerant to acetic acid stress.”
From Candida glabrata Biofilms: How Far Have We Come? (2017) · cites this paper as [209]
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Zhang, X., Nijland, J. G., & Driessen, A. J. M. (2022) · Research Square · doi:10.21203/rs.3.rs-1497017/v1
Zhang, X., Nijland, J. G., & Driessen, A. J. M. (2022) · Figshare · doi:10.6084/m9.figshare.20098825
Functional characterization of Candida auris DHA1 transporters conferring flucytosine resistance
Malik, S., Saini, A., Khatoon, R., & Banerjee, A. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2026.1806653
- Authors
- Costa, C., Henriques, A., Pires, C., Nunes, J., Ohno, M., Chibana, H., Sá-Correia, I., & Teixeira, M. C.
- Affiliations
- Institute for Biotechnology and Bioengineering (PT)
- Chiba University (JP)
- Corresponding author
- Teixeira, Miguel C.
- Venue
- Frontiers in Microbiology
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 4
- Pages
- 170-170
- ISSN
- 1664-302X (ISSN-L)
- PMC
- PMC3693063
- OpenAlex
- W2167191781
- Cited by
- 45
- References
- 44
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 8 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 1
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Microbiology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- Fundação para a Ciência e a Tecnologia (PTDC/EBB-BIO/119356/2010)
- National Institute of Allergy and Infectious Diseases
- 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, acetic acid resistance, antifungal resistance, 5-fluorocytosine, clotrimazole, plasma membrane localization, multidrug resistance
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