Disruption of the NAD cycle as a potential approach to manage fungal plant pathogens

Daniel Waiger Gautam Anand Yael Almog Shay Covo
Department of Plant Pathology and Microbiology, Robert H. Smith Faculty of Agriculture, The Hebrew University of Jerusalem, Rehovot, Israel

Fungal plant pathogens are major threat to food security and impose severe economic burden. Therefore, there is a continuous need to develop new strategies to manage fungal plant pathogens. We suggest the NAD pathway as a target for pesticide development. NAD oxidation status determines the metabolic fate of the cell. NAD is also consumed by sirtuins histone deacetylases. These proteins remove acetyl groups from histone and thus regulate gene expression and chromatin accessibility. Sirtuins convert NAD to nicotinamide; the latter is a vitamin that was shown to inhibit sirtuins. Wurtele et al. found that uptake of nicotinamide can reduce the severity of Candida albicans infection in mice. The mode of fungal toxicity was inhibition of the fungal specific sirtuin, Hst4. We were able to show that nicotinamide is fungistatic to plant pathogens albeit in high concentrations in vitro, on tomato slices and on cherry tomato berries. Nicotinamide inhibits hyphal growth much more than conidial germination. Fungal cells response to nicotinamide by over-expression of transcription factors in agreement with its role as a histone deacetylase inhibitor. In order to increase the efficiency of nicotinamide we thought to inhibit an enzyme that further metabolize it in the cell. Nicotinaldehyde inhibits in vitro pnc1 a nicotinamidase. Pnc1 is part of the NAD salvage pathway. Nicotinaldehyde is fungistatic but its mode of action is probably not through increase of the cellular concentration of nicotinamide. First, unlike nicotinamide, nicotinaldehyde inhibits germination much more than hyphal growth. Second, the cellular response to nicotinaldehyde is through over-expression of genes related to redox potential in the cell and not chromatin or transcription. Pnc1 is overexpressed by nicotinaldehyde suggesting it does inhibit the NAD salvage pathway. Currently, we further study the mode of action of nicotinamide and nicotinaldehyde in order to develop a novel strategy to manage fungal diseases.