Fungicidal Drugs Induce a Common Oxidative-Damage Cellular Death Pathway

SummaryAmphotericin, 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.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Fungicide-dependent reactive oxygen species production leads to fungal cellular death ► The TCA, ETC, and RAS/PKA pathways are involved in fungicide-induced cellular death ► Antifungals elevate mitochondrial activity, the AMP/ATP ratio, and sugar production ► DNA damage plays an important role in fungicide-induced cellular death