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Reference: Kim JH, et al. (2012) Targeting the oxidative stress response system of fungi with redox-potent chemosensitizing agents. Front Microbiol 3:88

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Abstract

The cellular antioxidant system is a target in the antifungal action of amphotericin B (AMB) and itraconazole (ITZ), in filamentous fungi. The sakADelta 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 mpkCDelta 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 sakADelta 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.

Reference Type
Journal Article
Authors
Kim JH, Chan KL, Faria NC, Martins Mde L, Campbell BC
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