The antifungal activity of cymoxanil is associated with proton pump inhibition and disruption of plasma membrane potential

Worldwide use of agrochemicals, particularly pesticides, is necessary to increase agricultural production to feed the ever-growing population. However, despite widespread use, the biochemical mode of action of many agrochemicals and their potential deleterious effects on the environment are poorly characterized. Cymoxanil (CYM) is a fungicide used to combat downy mildew diseases in grapevine cultures and late blight diseases in tomato and potato cultures caused by the oomycetes Plasmopara viticola and Phytophthora infestans, respectively. Previous reports indicate that CYM affects growth, DNA and RNA synthesis in Phytophthora and inhibits cell growth, biomass production and respiration rate in the well-characterized fungal model Saccharomyces cerevisiae. We therefore used this model to further dissect mechanisms underlying the toxicological effects of CYM. We found that CYM induced genome-wide alterations, particularly in membrane transporter systems. These alterations were associated with perturbations in lipid-raft organization and inhibition of Pma1p, leading to a decrease in plasma membrane potential and intracellular acidification. Altogether, these findings identify the plasma membrane as one of the targets of CYM and proposes a mode of action underlying its antifungal activity.