A β-carboline natural product induces oxidative stress in Fusarium graminearum and limits the virulence of multiple fungal phytopathogens

The emergence of fungicide-resistant pathogens of many agronomically important crop species necessitates the development of novel strategies for controlling diseases caused by fungi. β-carbolines encompass a wealth of natural products with diverse modes of action that lead to a myriad of phenotypic effects. While these molecules have been previously described as having antifungal activity against select species, the potential of β-carbolines to limit agricultural diseases caused by fungi has not been fully explored. Here, we report that several β-carbolines strongly inhibit growth and conidial germination in the devastating cereal pathogen Fusarium graminearum. We prioritized 1-carboxylic acid β-carboline (1-CABC) for downstream functional analyses, finding that, unlike the antioxidant properties of other, more commonly studied β-carbolines, 1-CABC induces oxidative stress and results in a loss of mitochondrial membrane potential. This bioactivity leads to a strong synergistic interaction with mitochondrial complex III inhibitors, including strobilurins, with the compound combination enhancing the induction of reactive oxygen species. We also showed that 1-CABC is effective as a single agent and in combination with strobilurins in models of infection for three fungal phytopathogens: F. graminearum, Botrytis cinerea, and Magnaporthe oryzae. Finally, we evaluated the effects of 1-CABC against a panel of diverse human fungal pathogens (encompassing both yeasts and molds). While 1-CABC antifungal activity is largely conserved across all fungi tested, the underlying mechanism(s) governing this bioactivity appear distinct. Collectively, these data strongly support future, more detailed mechanistic studies of 1-CABC against a range of fungal pathogens.IMPORTANCEFungal diseases are a major threat to global food production, and many crop pathogens are becoming resistant to existing fungicides. This study identifies a promising new strategy to combat these infections using a class of molecules called β-carbolines. Here, we found that one compound in particular, 1-carboxylic acid β-carboline (1-CABC), strongly blocks the growth of several destructive fungal pathogens, including Fusarium graminearum, a devastating pathogen of wheat. Unlike related compounds, 1-CABC increased the production of oxidative stress inside the pathogen, and importantly, the compound worked even better when combined with fungicides that inhibit mitochondrial function. The treatment was successful against multiple plant pathogens in infection models of plants, highlighting its potential for agricultural use. The study also showed activity against human fungal pathogens, although the mechanism responsible for this bioactivity appears distinct. Overall, this work highlights new antifungal strategies to protect crops, with the ultimate goal of improving food security.