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

我们之前的出版物已经证明了一种独特的超氧化物歧化酶（SOD）金属酶在革兰氏阳性致病菌金黄色葡萄球菌感染过程中的关键作用。这种金黄色葡萄球菌特异性超氧化物歧化酶在宿主定殖期间，细菌在体内经历宿主施加的锰饥饿期间，在维持强大的超氧化物防御中起关键作用。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研究其金属特异性。在这里，我们将(i)通过中子衍射（ND）确定超氧化物歧化酶的结构以定位质子/水，（ii）确定这种不寻常的超氧化物歧化酶的催化机制，（iii）测试现有的，并筛选新的化学抑制剂作为潜在的治疗线索和研究工具。ND的应用将有助于基础发现（确定作用机制和金属特异性），同时提供新的结构数据，为药物发现计划奠定基础。

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.