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      Fungicidal drugs induce a common oxidative-damage cellular death pathway.

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      Cell reports

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          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.

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          Author and article information

          Journal
          Cell Rep
          Cell reports
          2211-1247
          Feb 21 2013
          : 3
          : 2
          Affiliations
          [1 ] Howard Hughes Medical Institute, Boston University, Boston, MA 02215, USA.
          Article
          S2211-1247(13)00050-8 NIHMS459091
          10.1016/j.celrep.2012.12.021
          3656588
          23416050
          ed0b6d26-6a06-44ab-98ff-eebbc426af4d
          Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
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