Fungicidal drugs induce a common oxidative-damage cellular death pathway

Cell Rep. 2013 Feb 21;3(2):350-8. doi: 10.1016/j.celrep.2012.12.021. Epub 2013 Feb 14.


Amphotericin, miconazole, and ciclopirox are antifungal agents from three different drug classes that can effectively kill planktonic yeast, yet their complete fungicidal mechanisms are not fully understood. Here, we employ a systems biology approach to identify a common oxidative-damage cellular death pathway triggered by these representative fungicides in Candida albicans and Saccharomyces cerevisiae. This mechanism utilizes a signaling cascade involving the GTPases Ras1 and Ras2 and protein kinase A, and it culminates in death through the production of toxic reactive oxygen species in a tricarboxylic-acid-cycle- and respiratory-chain-dependent manner. We also show that the metabolome of C. albicans is altered by antifungal drug treatment, exhibiting a shift from fermentation to respiration, a jump in the AMP/ATP ratio, and elevated production of sugars; this coincides with elevated mitochondrial activity. Lastly, we demonstrate that DNA damage plays a critical role in antifungal-induced cellular death and that blocking DNA-repair mechanisms potentiates fungicidal activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphotericin B / pharmacology
  • Antifungal Agents / pharmacology*
  • Candida albicans / drug effects*
  • Candida albicans / metabolism
  • Ciclopirox
  • Citric Acid Cycle / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA Damage / drug effects
  • Electron Transport / drug effects
  • Fungal Proteins / metabolism
  • Metabolome
  • Miconazole / pharmacology
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Pyridones / pharmacology
  • Reactive Oxygen Species / metabolism
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism
  • ras Proteins / metabolism


  • Antifungal Agents
  • Fungal Proteins
  • Pyridones
  • Reactive Oxygen Species
  • Saccharomyces cerevisiae Proteins
  • Ciclopirox
  • Miconazole
  • Amphotericin B
  • Cyclic AMP-Dependent Protein Kinases
  • RAS1 protein, S cerevisiae
  • RAS2 protein, S cerevisiae
  • ras Proteins