Targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth and virulence

There is an urgent need to develop novel antifungals to tackle the threat that fungal pathogens pose to human health. In this work, we have performed a thorough characterisation and validation of the promising target methionine synthase. We have uncovered that in Aspergillus fumigatus the absence of its enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP. This drop in cell energetics prevents fungal growth, even in the presence of methionine. Using a tetOFF genetic model to mimic drug treatment we show that repression of methionine synthase in growing hyphae halts growth in vitro, which translates into a beneficial effect in vivo when targeting established infections. Finally, a structural-based virtual screening of methionine synthases reveals key differences between the human and fungal structures and unravels particularities of the fungal pockets that can direct the design of novel specific and broad-spectrum inhibitors. Therefore, methionine synthase is a valuable target for the development of new antifungals.