Engineering the yeast cytochrome bc1 complex for the development of new antifungal inhibitors
This project is awarded with a 4-year Norwich Research Park Biosciences Doctoral Training Partnership PhD CASE studentship with Syngenta. The studentship includes payment of tuition fees (directly to the University), a stipend to cover living expenses (2024/5 stipend rate: £19,237) and a CASE stipend enhancement of £4000pa, and a Research Training Support Grant of £5,000pa for each year of the studentship.
Cytochrome (cyt) bc1 complexes are central to electron transport chains in many species of bacteria and in mitochondria. The essentiality of this complex makes it a promising target for the development of new compounds that target human and plant pathogens. However, producing pure proteins from these pathogens in a laboratory environment is challenging because these organisms are often not genetically tractable, cannot be cultured on large scales, and can pose significant risks to researchers or the environment. Fungal pathogens of crop plants pose a major threat to global food security. Fungal diseases cause between 10% and 23% loss in global yields every year, which directly impacts availability and cost of food. Whilst there are many fungicides available to combat this issue, resistance is quick to develop meaning that new antifungal agents are urgently needed.
In collaboration with Syngenta, we are working on engineering the yeast cytochrome bc1 complex to generate a new model system for the rapid and safe development of new antifungal agents. We combine a suite of modern methods, including computational tools for protein engineering, structure determination by cryogenic electron microscopy, mechanistic studies by enzymology and electron paramagnetic resonance spectroscopy, and genetic engineering by CRISPR. The engineered organisms will provide an ideal platform to aid discovery of new inhibitors of this key enzyme and understand the mechanisms by which pathogens become resistant to fungicides.
Applications are encouraged from students interested in exploring the molecular mechanisms of enzymes using structural and computational methods. This project combines the skillsets of several laboratories spanning the Norwich Research Park and Syngenta to provide training in a suite of techniques, including molecular biology, computational protein engineering, enzymology, electron paramagnetic resonance spectroscopy and cryogenic electron microscopy.
For informal enquiries please contact Dr David Swainsbury (d.swainsbury@uea.ac.uk).
References
Swainsbury et al, PNAS (2023) https://doi.org/10.1073/pnas.2217922120
Swainsbury et al, BBA Bioenergetics (2018) https://doi.org/10.1016/j.bbabio.2017.12.005
Ding et al, BBA bioenergetics (2008) https://doi.org/10.1016%2Fj.bbabio.2008.04.029
Bonnefoy et al, Methods in Enzyology (2008) https://doi.org/10.1007%2F978-1-59745-365-3_11
MacMillan et al Applied Magnetic Resonance (2009) https://doi.org/10.1007/s00723-009-0077-4