title: Fungicidal drugs induce a common oxidative-damage cellular death pathway.
abstract: 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.
authors: Howard Hughes Medical Institute, Boston University, Boston, MA 02215, USA.
authors: Peter
authors: P
authors: Belenky
authors: Diogo
authors: D
authors: Camacho
authors: James J
authors: JJ
authors: Collins
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D000077768:Ciclopirox; D002952:Citric Acid Cycle / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D005656:Fungal Proteins / Q000378:metabolism; D055442:Metabolome; D008825:Miconazole / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D011728:Pyridones; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D000077768:Ciclopirox; D008825:Miconazole; D000666:Amphotericin B; D017868:Cyclic AMP-Dependent Protein Kinases; C489014:RAS1 protein, S cerevisiae; C489015:RAS2 protein, S cerevisiae; D018631:ras Proteins