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J. Biol. Chem., Vol. 278, Issue 31, 28831-28839, August 1, 2003

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Antifungal Activity of Amiodarone Is Mediated by Disruption of Calcium Homeostasis^*

Soma Sen Gupta   ¶, Van-Khue Ton  ¶, Veronica Beaudry ||, Samuel Rulli , Kyle Cunningham || and Rajini Rao  **

From the Departments of Physiology and ^||Biology, The Johns Hopkins University, Baltimore, Maryland 21205

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.

Received for publication, March 31, 2003 , and in revised form, May 7, 2003.

^* This work was funded by a Burroughs Wellcome Student Elective Prize (to S. S. G.) and by National Institutes of Health Grant GM62142 and a grant-in-aid from the American Heart Association Mid-Atlantic Affiliate (to R. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Lucy Cavendish College, University of Cambridge, Cambridge CB3 OBU, United Kingdom.

^¶ These authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Physiology, The Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205. Tel.: 410-955-4732; Fax: 410-955-0461; E-mail: rrao{at}jhmi.edu.

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