Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/2/2015
Publication Date: 11/10/2015
Publication URL: https://handle.nal.usda.gov/10113/61675
Citation: Kim, J.H., Chan, K.L., Mahoney, N.E. 2015. Augmenting the activity of monoterpenoid phenols against fungal pathogens using 2-hydroxy-4-methoxybenzaldehyde that target cell wall integrity. International Journal of Molecular Sciences. (16)26850-26870. doi: 10.3390/ijms161125988.
Interpretive Summary: The filamentous fungi in the genus Aspergillus or Penicillium are involved in food contamination, postharvest decay or human infection. For example, Aspergillus flavus/A. parasiticus or Penicillium expansum are the main producers of the mycotoxins aflatoxin or patulin, respectively, in crops. These mycotoxins cause serious health risks to human and animals. Mycotoxin contamination interferes with the safe production of crops, resulting in significantly negative impact on world economy. Considering the increasingly strict regulations worldwide, there is an urgent demand to develop methods for preventing mycotoxin contamination in agricultural commodities. Benzaldehyde derivatives are secondary metabolites produced by plants. In this study, bioassays are described using 2-hydroxy-4-methoxybenzaldehyde (2-OH-4-OMe), a benzaldehyde derivative, as chemosensitizing agent in combination with monoterpenoid phenols, where chemosensitization greatly enhance their antifungal activity. Chemosensitization also overcame the tolerance of fungal pathogens to fludioxonil, a commercial phenylpyrrole fungicide. Results showed that disruption of cell wall integrity systems is an effective strategy for control of fungal pathogens. Such disruption can be achieved with natural benzaldehyde derivatives that target cell wall integrity.
Technical Abstract: The aim of this study was to identify benzaldehydes to which the fungal cell wall integrity signaling mutants showed increased sensitivity. These compounds could then function as chemosensitizing agents in combination with monoterpenoid phenols, such as carvacrol or thymol, to enhance antifungal activity. Benzaldehydes were tested against strains of the model yeast Saccharomyces cerevisiae, i.e., wild type (WT) and slt2(delta) and bck1(delta), gene deletion mutants for the mitogen-activated protein kinase (MAPK) and MAPK kinase kinase (MAPKKK), respectively, in the cell wall integrity system. Among fifteen compounds tested, nine benzaldehydes were identified to increase the sensitivity of slt2(delta) and bck1(delta) mutants compared to the WT. Structure-activity relationship exists for the differential antifungal activity of compounds, where 2-hydroxy-4-methoxybenzaldehyde (2-OH-4-OMe) possessed the highest antifungal potency. The efficacy of 2-OH-4-OMe as an effective chemosensitizer was also tested in the filamentous fungi with methods outlined by the Clinical Laboratory Standards Institute (CLSI). Synergistic chemosensitization greatly lowers minimum inhibitory (MIC) or fungicidal (MFC) concentrations of test compounds. 2-OH-4-OMe also overcame the tolerance of two MAPK mutants of the filamentous fungal pathogen A. fumigatus (sakA(delta), mpkC(delta)) to fludioxonil, a phenylpyrrole fungicide. Natural benzaldehyde derivatives, such as 2-OH-4-OMe, effectively inhibit fungal growth. They possess chemosensitizing activity to enhance the efficacy of monoterpenoid phenols.