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A novel calcineurin-independent activity of cyclosporin A in Saccharomyces cerevisiae.
- Source :
-
Molecular bioSystems [Mol Biosyst] 2012 Oct; Vol. 8 (10), pp. 2575-84. - Publication Year :
- 2012
-
Abstract
- Fungi rely on regulatory networks to coordinate sensing of environmental stress with initiation of responses crucial for survival. Antifungal drugs are a specific type of environmental stress with broad clinical relevance. Small molecules with antifungal activity are ubiquitous in the environment, and are produced by a myriad of microbes in competitive natural communities. The echinocandins are fungal fermentation products and the most recently developed class of antifungals, with those in clinical use being semisynthetic derivatives that target the fungal cell wall by inhibiting 1,3-β-D-glucan synthase. Recent studies implicate the protein phosphatase calcineurin as a key regulator of cellular stress responses required for fungal survival of echinocandin-induced cell wall stress. Pharmacological inhibition of calcineurin can be achieved using the natural product and immunosuppressive drug cyclosporin A, which inhibits calcineurin by binding to the immunophilin Cpr1. This drug-protein complex inhibits the interaction between the regulatory and catalytic subunits of calcineurin, an interaction necessary for calcineurin function. Here, we report on potent activity of cyclosporin A when combined with the echinocandin micafungin against the model yeast Saccharomyces cerevisiae that is independent of its known mechanism of action of calcineurin inhibition. This calcineurin-independent synergy does not involve any of the 12 immunophilins known in yeast, individually or in combination, and is not mediated by any of the multidrug transporters encoded or controlled by YOR1, SNQ2, PDR5, PDR10, PDR11, YCF1, PDR15, ADP1, VMR1, NFT1, BPT1, YBT1, YNR070w, YOL075c, AUS1, PDR12, PDR1 and/or PDR3. Genome-wide haploinsufficiency profiling (HIP) and homozygous deletion profiling (HOP) strongly implicate the cell wall biosynthesis and integrity pathways as being central to the calcineurin-independent activity of cyclosporin A. Thus, systems level chemical genomic approaches implicate key cellular pathways in a novel mechanism of antifungal drug synergy.
- Subjects :
- Calcineurin metabolism
Carrier Proteins genetics
Carrier Proteins metabolism
Cell Wall metabolism
Drug Combinations
Drug Synergism
Haploinsufficiency
Immunophilins metabolism
Micafungin
Mutation
Pharmacogenetics
Saccharomyces cerevisiae metabolism
Saccharomyces cerevisiae Proteins metabolism
Signal Transduction drug effects
Antifungal Agents pharmacology
Cell Wall drug effects
Cyclosporine pharmacology
Echinocandins pharmacology
Genome, Fungal
Lipopeptides pharmacology
Saccharomyces cerevisiae drug effects
Saccharomyces cerevisiae genetics
Saccharomyces cerevisiae Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1742-2051
- Volume :
- 8
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular bioSystems
- Publication Type :
- Academic Journal
- Accession number :
- 22751784
- Full Text :
- https://doi.org/10.1039/c2mb25107h