Fungal diseases affect approximately 1.2 billion individuals worldwide with at least 1.5 million deaths each year. The emergence of resistant strains made clinical treatment failures more frequent. There is an urgent to treat drug resistant Candida spp. and Candida auris. In the UK, invasive and serious fungal disease impacts between 240k – 660k patients annually, causing more deaths than some superbugs.
Comparative genomics revealed fungal thioredoxin reductase 1 (Trr1) as an exciting new drug target as it is an essential gene only present in fungi but not in humans. This offers an exciting opportunity to develop a novel small-molecule intervention with broad spectrum single agent activity against clinically resistant fungi.
Target validation data thus far have been generated using trr1 null mutants. However, pharmacological intervention would never reach 100% target inhibition. Therefore, it is crucial to investigate how fungal pathogens respond to different levels of TRR1 inhibition to choose the minimum requirement of compounds and to pre-empt potential tolerance / resistance mechanisms.
In this exciting translational project, you will quantify Trr1 inhibition and fungal load responses to elucidate the pharmacodynamics of Trr1 inhibition in vitro and in vivo. You will then develop a Pharmacokinetics/Pharmacodynamics model to encompass the in vitro data on molecular and cellular levels, and then use this model to generate insights into how in vivo animal and human responses might be different from in vitro observations. You will also learn to apply disease modelling to analyse how patient survival is related to the fungal load and predict clinical treatment outcomes of a novel Trr1 therapy.
This project will equip you with the impressive skills in pharmacometrics and antimicrobial resistance, which will pave the way for a successful career in drug discovery and development.
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