Higher Degree by Research Application Portal

Multi-drug resistant bacteria are responsible for approximately 700,000 deaths per year, a figure which could reach 10 million by the year 2050. This project focuses on developing inhibitors of an endotoxin modifying enzyme that mediates antibiotic resistance by masking bacteria against both the human immune system and important classes of antibiotics. A structure guided approach will be used to develop novel therapeutic agents to treat MDR bacterial infections.

Project Goals:

Elucidate structures of the enzyme in complex with small molecule inhibitors using protein crystallography or cryo electron microscopy methods.

• Determine the binding affinities of the inhibitors for the enzyme.
• Use the structural information to optimize the inhibitors for enhanced potency.

Through this project you will:

• Acquire skills in recombinant protein expression and purification.

• Learn all aspects of protein crystallography and cryo electron microscopy to determine molecular structures to atomic resolution.

• Obtain expertise in other biochemical and biophysical methods used to characterize the protein and its interactions with small molecule inhibitors.

The project is multidisciplinary in that it provides opportunities for skills in structural biology, protein chemistry, biophysics and computational chemistry. You will work as a park of a team with medicinal chemists and microbiologists.

Self-funded applicants and scholarship holders. 

https://www.uwa.edu.au/study/courses/doctor-of-philosophy#fees-and-s...

https://www.uwa.edu.au/study/research/research-scholarships

Professor Alice Vrielink (alice.vrielink@uwa.edu.au)

https://research-repository.uwa.edu.au/en/persons/alice-vrielink

Our lab looks at the three dimensional structures of proteins implicated in disease. We are focused on proteins that act as virulence factors causing antibiotic resistance as well as proteins that are important in causing cancer and tumorigenesis. We characterize the structures of these proteins and study their interactions with small molecule inhibitors as part of the process of structure guided drug design.

A knowledge of proteins including their basic structures and function is important. Biochemistry laboratory skills is also required.

Reading

Anandan, A., Evans, G.L., Condic-Jurkic, K., O’Mara, M.L., John, C.M., Phillips, N.J., Jarvis, G.A., Wills, S.S., Stubbs, K.A., Moraes, I., Kahler, C.M. & Vrielink, A. (2017). Structure of a lipid A phosphoethanolamine transferase suggests how conformational changes govern substrate binding. Proceedings of the National Academy of Sciences USA, 114, 2218-2223.