Fungicidal activity of amiodarone is tightly coupled to calcium influx

Sabina Muend, Rajini Rao

Research output: Contribution to journalArticle

Abstract

The antiarrhythmic drug amiodarone has microbicidal activity against fungi, bacteria and protozoa. In Saccharomyces cerevisiae, amiodarone triggers an immediate burst of cytosolic Ca2+, followed by cell death markers. Ca2+ transients are a common response to many forms of environmental insults and toxic compounds, including osmotic and pH shock, endoplasmic reticulum stress, and high levels of mating pheromone. Downstream signaling events involving calmodulin, calcineurin and the transcription factor Crz1 are critical in mediating cell survival in response to stress. In this study we asked whether amiodarone induced Ca2+ influx was beneficial, toxic or a bystander effect unrelated to the fungicidal effect of the drug. We show that downregulation of Ca2+ channel activity in stationary phase cells correlates with increased resistance to amiodarone. In actively growing cells, extracellular Ca2+ modulated the size and shape of the Ca 2+ transient and directly influenced amiodarone toxicity. Paradoxically, protection was achieved both by removal of external Ca 2+ or by adding high levels of CaCl2 (10 mM) to block the drug induced Ca2+ burst. Our results support a model in which the fungicidal activity of amiodarone is mediated by Ca2+ stress, and highlight the pathway of Ca2+ mediated cell death as a promising target for antifungal drug development.

Original languageEnglish (US)
Pages (from-to)425-431
Number of pages7
JournalFEMS Yeast Research
Volume8
Issue number3
DOIs
StatePublished - May 1 2008

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Keywords

  • Amiodarone
  • Calcium influx
  • Calcium stress
  • Cell death
  • Fungicide

ASJC Scopus subject areas

  • Microbiology
  • Applied Microbiology and Biotechnology

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