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Calcium-Activated-Calcineurin Reduces the In Vitro and In Vivo Sensitivity of Fluconazole to Candida albicans via Rta2p
- Source :
- PLoS ONE, PLoS ONE, Vol 7, Iss 10, p e48369 (2012)
- Publication Year :
- 2012
- Publisher :
- Public Library of Science, 2012.
-
Abstract
- 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.
- Subjects :
- Antifungal Agents
lcsh:Medicine
Yeast and Fungal Models
Pharmacology
Mice
hemic and lymphatic diseases
Gene Expression Regulation, Fungal
Molecular Cell Biology
Candida albicans
Signaling in Cellular Processes
lcsh:Science
Fluconazole
Fungal protein
Multidisciplinary
biology
Calcineurin
Fungal Diseases
Corpus albicans
Signaling Cascades
Infectious Diseases
Medicine
Female
medicine.drug
Research Article
Signal Transduction
Mycology
Microbiology
Signaling Pathways
Fungal Proteins
Systemic Mycoses
Model Organisms
In vivo
Drug Resistance, Fungal
medicine
Calcium-Mediated Signal Transduction
Animals
Calcium Signaling
Biology
lcsh:R
Cell Membrane
Fungi
Candidemia
medicine.disease
biology.organism_classification
In vitro
Enzyme Activation
Calcium Signaling Cascade
lcsh:Q
Calcium
Systemic candidiasis
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 7
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....d332e1b6c95687afb8bc6f29539718d7