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Front Microbiol. 2012 Mar 16;3:88. doi: 10.3389/fmicb.2012.00088. eCollection 2012.

Targeting the oxidative stress response system of fungi with redox-potent chemosensitizing agents.

Author information

  • 1Plant Mycotoxin Research Unit, Western Regional Research Center, USDA-ARS Albany, CA, USA.

Abstract

The cellular antioxidant system is a target in the antifungal action of amphotericin B (AMB) and itraconazole (ITZ), in filamentous fungi. The sakAΔ mutant of Aspergillus fumigatus, a mitogen-activated protein kinase (MAPK) gene deletion mutant in the antioxidant system, was found to be more sensitive to AMB or ITZ than other A. fumigatus strains, a wild type and a mpkCΔ mutant (a MAPK gene deletion mutant in the polyalcohol sugar utilization system). Complete fungal kill (≥99.9%) by ITZ or AMB was also achieved by much lower dosages for the sakAΔ mutant than for the other strains. It appears msnA, an Aspergillus ortholog to Saccharomyces cerevisiaeMSN2 (encoding a stress-responsive C(2)H(2)-type zinc-finger regulator) and sakA and/or mpkC (upstream MAPKs) are in the same stress response network under tert-butyl hydroperoxide (t-BuOOH)-, hydrogen peroxide (H(2)O(2))- or AMB-triggered toxicity. Of note is that ITZ-sensitive yeast pathogens were also sensitive to t-BuOOH, showing a connection between ITZ sensitivity and antioxidant capacity of fungi. Enhanced antifungal activity of AMB or ITZ was achieved when these drugs were co-applied with redox-potent natural compounds, 2,3-dihydroxybenzaldehyde, thymol or salicylaldehyde, as chemosensitizing agents. We concluded that redox-potent compounds, which target the antioxidant system in fungi, possess a chemosensitizing capacity to enhance efficacy of conventional drugs.

KEYWORDS:

Aspergillus; Candida; Cryptococcus; amphotericin B; chemosensitization; itraconazole; natural compounds; oxidative stress response

PMID:
22438852
[PubMed]
PMCID:
PMC3305922
Free PMC Article

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