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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Belenky P,Camacho D,Collins JJ

doi

10.1016/j.celrep.2012.12.021

subject

Has Abstract

pub_date

2013-02-21 00:00:00

pages

350-8

issue

2

issn

2211-1247

pii

S2211-1247(13)00050-8

journal_volume

3

pub_type

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