Inhibition of Aspergillus fumigatus thioredoxin reductase by ebselen: a promising antifungal drug

Aspergillus fumigatus infections are increasing in incidence and are associated with high mortality rates, high cost of treatment and longer hospital stays. In addition, the limitations of current effective antifungals and increasing antifungal resistance highlight the need for the development of new antifungals with novel targets. Thioredoxin reductase catalyses the reduction of thioredoxin by NADPH, and is responsible for maintaining a reducing intracellular environment and acting as an electron donor for various biosynthetic enzymes. It has been shown to be essential for the growth of A. fumigatus and therefore presents as a potential target for novel antifungals. The aims of this project are to gain a detailed knowledge of the molecular mechanisms underlying its function by X-ray crystallography, and identify small molecule inhibitors that may serve as lead compounds for the development of novel antifungals. To date, we have successfully solved the structure of A. fumigatus thioredoxin reductase in complex with FAD and NADPH to 3.2Å, and shown that Ebselen – a small drug-like molecule – is a nanomolar inhibitor of the enzyme in vitro and also inhibits growth of Aspergillus spp. with MIC values of 16 to 64 µg/ml. Using mass spectrometry we have also demonstrated that Ebselen interacts covalently with a specific catalytic cysteine. Current work is focussed on solving the structure of the enzyme in complex with Ebselen in order to define interactions at an atomic level which are important for inhibition of the enzyme, providing a scaffold for future design of specific and potent anti-Aspergillus drugs that target thioredoxin reductase.