Structure and function of bacterial GTPases - emerging new targets for antimicrobial drug design

Bacterial pathogens are responsible for a significant amount of disease and morbidity worldwide. Bacteria can become resistant to antibiotics resulting in one of the biggest challenges facing modern society and highlighting the need for the identification of new drug targets. Recently we identified a family of GTPases with roles in ribosome assembly. We have shown that the activities of these enzymes are essential for ribosome biogenesis and bacterial growth, making them novel targets for broad-spectrum antibiotic discovery. To develop inhibitors, it is vital that we understand the 3D molecular architecture of the ribosome in complex with GTPase cofactors. Then we can begin to understand how disruption of these enzymes changes both the structure and function of the ribosome. To achieve this, we will exploit exciting new developments in microscopy - cryo-electron microscopy - that allow us to visualize ribosomes in fine detail. We will determine the binding site of these GTPases and map defects that arise in their absence. Additionally, a small nucleotide inhibitor of these GTPases is available. Its impact on ribosome maturation and bacterial viability will be interrogated. This project will provide the student with thorough training in microbiology, antibiotic susceptibility testing, biochemical assays and advanced electron imaging approaches.