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

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.