Calcium-activated-calcineurin reduces the in vitro and in vivo sensitivity of fluconazole to Candida albicans via Rta2p
Open accessAbstract
Due to the emergence of drug-resistance, first-line therapy with fluconazole (FLC) increasingly resulted in clinical failure for the treatment of candidemia. Our previous studies found that in vitro RTA2 was involved in the calcineurin-mediated resistance to FLC in C. albicans. In this study, we found that calcium-activated-calcineurin significantly reduced the in vitro sensitivity of C. albicans to FLC by blocking the impairment of FLC to the plasma membrane via Rta2p. Furthermore, we found that RTA2 itself was not involved in C. albicans virulence, but the disruption of RTA2 dramatically increased the therapeutic efficacy of FLC in a murine model of systemic candidiasis. Conversely, both re-introduction of one RTA2 allele and ectopic expression of RTA2 significantly reduced FLC efficacy in a mammalian host. Finally, we found that calcium-activated-calcineurin, through its target Rta2p, dramatically reduced the efficacy of FLC against candidemia. Given the critical roles of Rta2p in controlling the efficacy of FLC, Rta2p can be a potential drug target for antifungal therapies.
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RTA2 gene encoding a flippase is the target for calcineurin-mediated azole resistance via its transcriptional factor Crz1p.
“This was further linked to the RTA2 gene encoding a flippase as the target for calcineurin-mediated azole resistance via its transcriptional factor Crz1p (Jia et al., 2009; Jia et al., 2012).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Jia et al., 2012
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- Authors
- Jia, Y., Tang, R.-J., Wang, L., Zhang, X., Wang, Y., Jia, X.-M., & Jiang, Y.-Y.
- Affiliations
- Tongji University (CN)
- Second Military Medical University (CN)
- Corresponding author
- Jia, Xin-Ming
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-10-30
- Volume
- 7
- Issue
- 10
- Pages
- e48369
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3484117
- OpenAlex
- W2073880101
- Cited by
- 19
- References
- 56
- Citations by year
- 2025: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 1 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 1
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-01-03)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (90913008, 30900055)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- calcineurin, fluconazole resistance, Candida albicans, candidemia, systemic candidiasis, antifungal resistance, plasma membrane, drug efflux, virulence, antifungal drug targets
- MeSH terms
- Animals, Antifungal Agents, Calcium, Candida albicans, Cell Membrane, Enzyme Activation, Female, Fungal Proteins, Fluconazole, Gene Expression Regulation, Fungal, Calcineurin, Drug Resistance, Fungal, Mice, Candidemia
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