Cinnamic acid analogs as intervention catalysts for overcoming antifungal tolerance

Authors: KIM, JONG - Former ARS Employee; Chan, Kathleen - Kathy; Cheng, Luisa

Submitted to: Molecules
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/19/2017
Publication Date: 10/21/2017
Citation: Kim, J., Chan, K.L., Cheng, L.W. 2017. Cinnamic acid analogs as intervention catalysts for overcoming antifungal tolerance. Molecules. 22(10):1783. https://doi.org/10.3390/molecules22101783.
DOI: https://doi.org/10.3390/molecules22101783

Interpretive Summary: Due to increasing concerns about the safety of certain antifungal drugs that have been in wide use, and the impact of repeated exposure to these compounds on health and fungal resistance, there are constant demands for new antifungals or drug potentiators with improved health and safety profiles. Many natural products, such as cinnamic acids, are “generally recognized as safe” compounds, and are potential sources of antifungal agents, either in their intact structure or as lead compounds for more potent structural analogs. We found cinnamic acids could augment the efficacy of cell wall-disrupting antifungal agents. Cinnamic acid-mediated chemosensitization also overcame the tolerance of fungal pathogens to fludioxonil, a commercial phenylpyrrole fungicide. Threrfore, it is concluded that cinnamic acid derivatives investigated in this study could be developed as promising intervention catalysts for effective control of fungal pathogens.

Technical Abstract: Antifungal potency of thirty-three cinnamic acid derivatives was investigated. The efficacy of caspofungin (CAS) or octyl gallate (OG), the cell wall disrupting agents, was augmented by 4-chloro-a-methyl- or 4-methylcinnamic acid screened. Synergistic chemosensitization by 4-chloro-a-methyl- or 4-methylcinnamic acid greatly lowers minimum inhibitory concentrations of antifungal agents co-administered. 4-Chloro-a-methylcinnamic acid further overcame fludioxonil tolerance of Aspergillus fumigatus mutants. 4-Methylcinnamic acid, the deoxygenated structure of 4-methoxycinnamic acid, also overcame tolerance of glutathione reductase mutant to 4-methoxycinnamic acid, indicating the importance of para substitution of methyl moiety for improved antifungal activity. Collectively, 4-chloro-a-methyl- or 4-methylcinnamic acids possess chemosensitizing capability to enhance the efficacy of CAS, OG or fludioxonil, thus can be developed as target-based (namely, cell wall disruption) intervention catalysts.