High Resolution Structural Characterisation and Structure-Based Drug Discovery Targeting a Crucial Metalloenzyme of Methicillin Resistant Staphylococc

针对耐甲氧西林葡萄球菌的关键金属酶的高分辨率结构表征和基于结构的药物发现

• 批准号: 2601861
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2601861
• 关键词: Resolution; Structural; Characterisation; Structure; Based

Our prior publications have demonstrated a crucial role for a unique superoxide dismutase (SOD) metalloenzyme in the Gram positive pathogenic bacterium Staphylococcus aureus during infection. This S. aureus-specific SOD plays a key role in enabling a robust superoxide defence to be maintained during the host-imposed manganese starvation the bacterium experiences in vivo during host colonisation. We have determined X-ray crystal structures and performed detailed biochemistry to study its metal specificity. Here, we will (i) determine the SOD structure by neutron diffraction (ND) to localise protons/waters, (ii) determine the catalytic mechanism of this unusual SOD, and (iii) test existing, and screen for novel chemical inhibitors as potential therapeutic leads and as research tools. Application of ND will enable fundamental discoveries (determining mechanism of action and of metal specificity) while providing novel structural data that will underpin drug discovery programs.

我们先前的出版物表明，在感染期间，在革兰氏阳性致病细菌金黄色葡萄球菌中，独特的超氧化物歧化酶（SOD）金属酶的作用至关重要。这款金黄色葡萄球菌特异性的草皮在使宿主型锰饥饿期间保持稳健的超氧化防御能力在宿主殖民期间体内的细菌体验在体内实现。我们已经确定了X射线晶体结构，并进行了详细的生物化学来研究其金属特异性。在这里，我们将（i）通过中子衍射（ND）确定SOD结构以定位质子/水，（ii）确定这种不寻常的SOD的催化机制，以及（iii）测试现有的，并筛选出新的化学抑制剂作为潜在的治疗铅和研究工具。 ND的应用将实现基本发现（确定作用机理和金属特异性的机理），同时提供新的结构数据，以基于药物发现计划。