Abstract
BackgroundDisruption of cellular antioxidation systems should be an effective method for control of fungal pathogens. Such disruption can be achieved with redox-active compounds. Natural phenolic compounds can serve as potent redox cyclers that inhibit microbial growth through destabilization of cellular redox homeostasis and/or antioxidation systems. The aim of this study was to identify benzaldehydes that disrupt the fungal antioxidation system. These compounds could then function as chemosensitizing agents in concert with conventional drugs or fungicides to improve antifungal efficacy.MethodsBenzaldehydes were tested as natural antifungal agents against strains of Aspergillus fumigatus, A. flavus, A. terreus and Penicillium expansum, fungi that are causative agents of human invasive aspergillosis and/or are mycotoxigenic. The yeast Saccharomyces cerevisiae was also used as a model system for identifying gene targets of benzaldehydes. The efficacy of screened compounds as effective chemosensitizers or as antifungal agents in formulations was tested with methods outlined by the Clinical Laboratory Standards Institute (CLSI).ResultsSeveral benzaldehydes are identified having potent antifungal activity. Structure-activity analysis reveals that antifungal activity increases by the presence of an ortho-hydroxyl group in the aromatic ring. Use of deletion mutants in the oxidative stress-response pathway of S. cerevisiae (sod1Δ, sod2Δ, glr1Δ) and two mitogen-activated protein kinase (MAPK) mutants of A. fumigatus (sakAΔ, mpkCΔ), indicates antifungal activity of the benzaldehydes is through disruption of cellular antioxidation. Certain benzaldehydes, in combination with phenylpyrroles, overcome tolerance of A. fumigatus MAPK mutants to this agent and/or increase sensitivity of fungal pathogens to mitochondrial respiration inhibitory agents. Synergistic chemosensitization greatly lowers minimum inhibitory (MIC) or fungicidal (MFC) concentrations. Effective inhibition of fungal growth can also be achieved using combinations of these benzaldehydes.ConclusionsNatural benzaldehydes targeting cellular antioxidation components of fungi, such as superoxide dismutases, glutathione reductase, etc., effectively inhibit fungal growth. They possess antifungal or chemosensitizing capacity to enhance efficacy of conventional antifungal agents. Chemosensitization can reduce costs, abate resistance, and alleviate negative side effects associated with current antifungal treatments.
Highlights
Disruption of cellular antioxidation systems should be an effective method for control of fungal pathogens
Microorganisms Aspergillus fumigatus AF293, and A. fumigatus mitogen-activated protein kinase (MAPK) deletion mutants sakAΔ and mpkCΔ [43,44] were grown at 35°C on potato dextrose agar (PDA)
We tested eleven conventional antifungal agents, which disrupt the functions of complexes I, II, III, IV or alternative oxidases (AOX) in the mitochondrial respiratory chain (MRC), using A. fumigatus AF293 as a representative fungal pathogen (Figure 1A)
Summary
Disruption of cellular antioxidation systems should be an effective method for control of fungal pathogens. The aim of this study was to identify benzaldehydes that disrupt the fungal antioxidation system These compounds could function as chemosensitizing agents in concert with conventional drugs or fungicides to improve antifungal efficacy. Prior studies showed that analogs of benzoic or cinnamic acids, common phenolics found in edible plants, inhibit biosynthesis of mycotoxins and growth of various fungi, both filamentous and yeasts [10,11,12]. Noteworthy is that these phenolics can be potent redox cyclers that inhibit microbial growth through disruption of cellular redox homeostasis and/or antioxidation systems [13,14]
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