Gupta SS~Rao R, 2003

Pubmed ID 12754197
Title Antifungal activity of amiodarone is mediated by disruption of calcium homeostasis.
Authors Soma Sen Gupta, Van-Khue Ton, Veronica Beaudry, Samuel Rulli, Kyle Cunningham, Rajini Rao
Abstract The antiarrhythmic drug amiodarone was recently demonstrated to have novel broad range fungicidal activity. We provide evidence that amiodarone toxicity is mediated by disruption of Ca2+ homeostasis in Saccharomyces cerevisiae. In mutants lacking calcineurin and various Ca2+ transporters, including pumps (Pmr1 and Pmc1), channels (Cch1/Mid1 and Yvc1), and exchangers (Vcx1), amiodarone sensitivity correlates with cytoplasmic calcium overload. Measurements of cytosolic Ca2+ by aequorin luminescence demonstrate a biphasic response to amiodarone. An immediate and extensive calcium influx was observed that was dose-dependent and correlated with drug sensitivity. The second phase consisted of a sustained release of calcium from the vacuole via the calcium channel Yvc1 and was independent of extracellular Ca2+ entry. To uncover additional cellular pathways involved in amiodarone sensitivity, we conducted a genome-wide screen of nearly 5000 single-gene yeast deletion mutants. 36 yeast strains with amiodarone hypersensitivity were identified, including mutants in transporters (pmr1, pdr5, and vacuolar H+-ATPase), ergosterol biosynthesis (erg3, erg6, and erg24), intracellular trafficking (vps45 and rcy1), and signaling (ypk1 and ptc1). Of three mutants examined (vps45, vma3, and rcy1), all were found to have defective calcium homeostasis, supporting a correlation with amiodarone hypersensitivity. We show that low doses of amiodarone and an azole (miconazole, fluconazole) are strongly synergistic and exhibit potent fungicidal effects in combination. Our findings point to the potentially effective application of amiodarone as a novel antimycotic, particularly in combination with conventional antifungals.
Citation J. Biol. Chem. 2003; 278:28831-9

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Papers Phenotype Conditions Collection Tested mutants Data Details
Gupta SS~Rao R, 2003 growth (culture turbidity) amiodarone [7 uM] hap alpha ~5,000 Discrete

Curation history

June 13, 2013 Data requested.
Sept. 16, 2013 Data requested.
May 13, 2014 Data abandoned.
Feb. 16, 2015 Tested strains abandoned.
Feb. 16, 2015 Data to load.
Sept. 14, 2016 Data loaded.