Fungal infections have major socioeconomic impacts. Recent estimates suggest that invasive human fungal infections kill more than 1.6 million people annually and that 600 million people could be fed each year by halting the spread of fungal diseases in the five most important crops. A range of antifungals, although relatively limited, are currently used to control fungal pathogens, but resistance to those is growing, underscoring the urgent need for new molecular targets and treatments.
Iron-sulphur (Fe-S) clusters are inorganic cofactors found in all kingdoms of life and are required for several essential cellular processes such as oxidative phosphorylation, DNA synthesis and repair, iron metabolism. Pathways involved in the biogenesis of Fe-S proteins were suggested to represent possible novel antifungal targets. The main objective of the project was to establish the essential mitochondrial and cytoplasmic NADPH-dependent electron transfer chains (Arh1-Yah1 and Tah18-Dre2, respectively) as novel antifungal targets by discovering compounds that can disrupt the interaction and therefore the function of Arh1-Yah1 and Tah18-Dre2. By screening the libraries of the Institut de Chimie des Substances Naturelles (ICSN, CNRS, Gif-sur-Yvette, France) against the yeast Saccharomyces cerevisiae, several natural compounds and extracts have been found to potentially inhibit the interaction between the mitochondrial ferredoxin Yah1 and its reductase Arh1. Additionally, synergy was found between these compounds and the antimalarial primaquine, a drug that, as we showed previously, targets Fe-S proteins such as the aconitase of the tricarboxylic acid cycle and Rli1, a protein essential for ribosome biogenesis and protein translation. Synergistic combinations allow to lower cost and potential toxicity by reducing doses needed to inhibit fungal growth. This strategy is particularly useful when the protein targeted is relatively well conserved between the organism pathogens and their hosts, like here. The paucity of current antifungal treatments can actually be partly explained by the common eukaryotic nature of fungal pathogens and their hosts. Therefore, finding fungal-specific agents is challenging and synergistic combinations of agents can be a way to minimize this challenge. Synergistic effects are seen where agents target a common process but by different mechanisms or pathways. Therefore, targeting for instance the ferredoxin Yah1 and a protein of its protein network could be a promising strategy to inhibit fungal pathogens. Unfortunately, we have currently very limited information regarding the protein network of the ferredoxin. Another objective of this project was therefore to develop a range of tools to establish this network and identified novel antifungal targets within.
The data collectively support the mitochondrial NADPH-dependent electron transfer chain as a potential antifungal target and highlight promising drug candidates.
