About the project
In this project you will investigate the mechanism of how fungi rewire cellular signalling and metabolism to rapidly adapt to lethal levels of stress. The work will involve live cell imaging, super resolution imaging, molecular biology, and proteomics. You will also perform metabolic analysis on populations of yeast and live cells. The project has implications for microbial drug resistance, virulent fungi such as Candida, and chemotherapy resistance in cancer cells.
A few individual cells persist, adapt and survive when pathogenic cells are targeted by a drug, leading to a recurrence of disease that is resistant to the initial drug. Drug resistant fungal infections account for millions of deaths every year. You would with this PhD investigate the mechanism of persistence in fungi, based on new clues about how drug resistant cells evolve.
You will use baker’s yeast as a model system. It is one of the most sophisticated experimental systems that has ever been designed, with exquisitely precise tools available for genetic manipulation, protein tagging, biochemistry, cell biology, and other methods of delving into the molecular details of biological mechanisms.
We hypothesise that a universal requirement of evolving persistence is a sequence of metabolic adaptations. To survive lethal amounts of a drug, cells must cease their metabolic activity and go into a state of partial dormancy. They must then turn on key survival mechanisms, including a way of producing energy in a dormant state. Finally, they must exit dormancy and become highly flexible in the food source that they use for growth.
Recent studies, and particularly work from our group, have provided clues as to the workings of metabolic adaptation to severe stress. When faced with difficult conditions, cells form internal structures called stress granules. These structures act like signaling command centers, and are able to generate multiple protective responses, including initiation of dormancy and metabolic adaptation.
We aim to dissect the molecular details of this mechanism and demonstrate a proof of concept for targeting stress granules and metabolism in anti-fungal drug discovery. This project will make major contributions to our understanding of drug resistance and will enable new platforms for drug discovery.
