Redox-active antifungals that target stress defense system in fungi

The antifungal mechanisms of redox-active drugs or leads such as polyenes involve the oxidative stress response in pathogens. Redox-active molecules can function as potent redox-cyclers in fungi, which contribute to the disruption of cellular redox homeostasis or redox-sensitive components. Using the model yeast Saccharomyces cerevisiae as a screening tool, we determined how the redox-active 2-hydroxy-4-methoxybenzaldehyde (2H4M) negatively affected both the antioxidant and cell wall integrity systems of fungi, indicating a crosstalk between the two systems under 2H4M-induced stress. This crosstalk contributes to the fungal defense against redox-active molecules, and therefore, could be an effective target for antifungal treatment.

Meanwhile, the redox-active polyene drug natamycin has also been used in industry for the control of foodborne- and agricultural fungal pathogens. Studies indicated that invasive fungal infections in humans by Candida, Aspergillus species, etc., could be acquired from contaminated food or nutritional supplements. Accordingly, there have been discussions whether natamycin as a food additive/fungicide can trigger the emergence of human pathogens that are cross-resistant to multiple polyenes (amphotericin B, nystatin, natamycin) via food sources. We examined the antifungal efficacy of natamycin against mycotoxin-producing, heat-resistant and invasive fungi, and found differential susceptibility of the test strains to natamycin under different pHs, namely high versus low acidity. Our data provide information that acknowledges the importance of One Health approach, and could improve the safe, effective use of natamycin, thus enhancing food safety and public health. The control of fungal pathogens resistant to other drugs is discussed further.