Submitted to: Journal of Applied Microbiology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 11/24/2005
Publication Date: 4/15/2006
Citation: Kim, J.H., Campbell, B.C., Mahoney, N.E., Chan, K.L., May, G.S. 2006. Targeting antioxidative signal transduction and stress response system: control of pathogenic Aspergillus with phenolics that inhibit mitochondrial function. Journal of Applied Microbiology. 101(1):181-189. Interpretive Summary: Many fungi present a health problem. Some fungi produce toxins that are either poisonous or carcinogenic. Other fungi can directly infect tissues and cause severe damage to vital organs. One group of fungi that produce toxins and can infect humans are in the genus Aspergillus. While there are many commercial products that can be used to kill fungi, fungicides, either in agricultural settings or as drugs, they are expensive and many fungi eventually develop resistance to them. This study attempts to find specific genes in these fungi that can be targeted by safe, natural chemicals. By targeting such genes, the effectiveness of fungicides or fungicidial drugs can be greatly augmented. Here, we show that genes involved with the ability of fungi to respond to certain stresses make good targets using certain compounds. By treating fungi with these compounds and commercially available fungicides we were able to elevate the effectiveness of the fungicides 100 to 1,000 fold. This higher activity allows reduced amounts of fungicides to be effective, thus lowering treatment costs and potential for development of resistance.
Technical Abstract: Selected phenolic acids and their structural derivatives are used in target-gene based bioassays using the yeast Saccharomyces cerevisiae to determine their impact on mitochondrial respiration. Effective compounds are used in combination with known fungicides against the aspergilli to examine synergism predicated on disruption of antioxidative stress response systems. Exemplary target-gene bioassays were performed using a sakA(delta) strain of A. fumigatus (a deletion mutant missing a MAPK gene responsive to osmotic stress/nutritional sensing) and a complementation analysis using the mitochondrial superoxide dismutase (Mn-SOD) gene (sodA) of A. flavus in the ortholog mutant, sod2(delta), of S. cerevisiae. The results of these assays demonstrated signal transduction and the mitochondrial antioxidative stress system play important roles in fungal response/tolerance to antifungal agents tested. Thus, certain natural compounds, such as the phenolics used in this study, that do not pose any significant medical or environmental risks, could serve as useful alternatives or additives to conventional antifungal agents.