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

细菌病原体是全世界相当数量的疾病和发病率的罪魁祸首。细菌可能对抗生素产生抗药性，导致现代社会面临的最大挑战之一，并突显了确定新药物靶点的必要性。最近，我们发现了一个在核糖体组装中起作用的GTP酶家族。我们已经证明，这些酶的活性对于核糖体的生物发生和细菌生长是必不可少的，使它们成为广谱抗生素发现的新靶点。为了开发抑制剂，了解核糖体与GTP酶辅助因子形成的复合体的三维分子结构是至关重要的。然后我们就可以开始了解这些酶的破坏是如何改变核糖体的结构和功能的。为了实现这一点，我们将利用显微镜-低温电子显微镜-的令人兴奋的新发展，使我们能够看到核糖体的精细细节。我们将确定这些GTP酶的结合位置，并绘制在它们缺失时出现的缺陷图。此外，这些GTP酶的一种小核苷酸抑制剂也是可用的。它对核糖体成熟和细菌存活的影响将被询问。该项目将为学生提供在微生物学、抗生素敏感性测试、生化分析和先进的电子成像方法方面的全面培训。

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.