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 cerevisiae MSN2 (encoding a stress-responsive C2H2-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 (H2O2)- 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.
Highlights
Recent studies have shown that one of the antimicrobial modes of action of certain drugs involves cellular oxidative stress response in pathogens, which further contributes to the death of microorganisms
ASPERGILLUS mitogen-activated protein kinase (MAPK) AND msnA MUTANTS WERE SENSITIVE TO OXIDATIVE STRESS We initially investigated the phenotypic responses of three Aspergillus mutant strains, i.e., deletion mutants for A. fumigatus MAPKs, sakA and mpkC, and A. flavus msnA genes, to t -BuOOH and H2O2
All three Aspergillus mutants, i.e., A. fumigatus sakAΔ and mpkCΔ, A. flavus CA14msnAΔ, showed marginally higher sensitivity to t -BuOOH and H2O2 compared to the wild type strains (Data not shown)
Summary
Recent studies have shown that one of the antimicrobial modes of action of certain drugs involves cellular oxidative stress response in pathogens, which further contributes to the death of microorganisms. These types of drugs could be defined as oxidative stress drugs. Other studies further support involvement of cellular oxidative stress as a component of the antifungal mode of action of AMB (SokolAnderson et al, 1986, 1988; Blum et al, 2008; An et al, 2009; González-Párraga et al, 2011)
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