Related Experiment Video
Updated: May 23, 2026
Methods to Inhibit Bacterial Pyomelanin Production and Determine the Corresponding Increase in Sensitivity to Oxidative Stress
Published on: August 31, 2015
Targeting the oxidative stress response system of fungi with redox-potent chemosensitizing agents
Jong H Kim1, Kathleen L Chan, Natália C G Faria
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.
Insights
The antioxidant system impacts antifungal drug efficacy. Deleting the sakA gene in Aspergillus fumigatus increased sensitivity to amphotericin B (AMB) and itraconazole (ITZ), suggesting targeting this system enhances drug effectiveness.
Area of Science:
- Mycology
- Antifungal Drug Discovery
- Cellular Stress Response
Background:
- The cellular antioxidant system plays a role in the antifungal mechanisms of amphotericin B (AMB) and itraconazole (ITZ) in filamentous fungi.
- The sakA gene, encoding a mitogen-activated protein kinase (MAPK), is crucial for the antioxidant response in Aspergillus fumigatus.
Purpose of the Study:
- To investigate the role of the sakA gene and the broader antioxidant system in fungal sensitivity to AMB and ITZ.
- To explore the potential of targeting fungal antioxidant pathways to enhance antifungal drug efficacy.
Main Methods:
- Comparative analysis of antifungal drug sensitivity in Aspergillus fumigatus strains with varying antioxidant system components (wild type, sakAΔ mutant, mpkCΔ mutant).
- Assessment of fungal viability and required drug dosages for complete fungal kill.
- Investigation of the link between drug sensitivity and antioxidant capacity using oxidative stress agents like tert-butyl hydroperoxide (t-BuOOH) and hydrogen peroxide (H(2)O(2)).
- Evaluation of the chemosensitizing effects of natural redox-potent compounds (2,3-dihydroxybenzaldehyde, thymol, salicylaldehyde) when combined with AMB or ITZ.
Main Results:
- The sakAΔ mutant exhibited significantly higher sensitivity to AMB and ITZ compared to wild-type and mpkCΔ strains.
- Lower dosages of AMB or ITZ were required to achieve complete fungal kill (≥99.9%) in the sakAΔ mutant.
- A correlation was observed between itraconazole (ITZ) sensitivity in yeast pathogens and their sensitivity to oxidative stress (t-BuOOH), indicating a link to antioxidant capacity.
- Co-application of AMB or ITZ with natural redox-potent compounds enhanced the antifungal activity of the conventional drugs.
Conclusions:
- The sakA gene and potentially other components of the stress response network (e.g., msnA, mpkC) are integral to fungal tolerance against oxidative stress and antifungal drugs.
- Targeting the fungal antioxidant system can enhance the efficacy of existing antifungal agents like AMB and ITZ.
- Redox-potent natural compounds demonstrate chemosensitizing capacity, offering a strategy to improve conventional antifungal therapies.
Related Concept Videos
01:15Antifungal Agents
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...