About the Project
Novel classes of antibiotics are urgently needed to combat the emergence and global spread of antimicrobial resistance (AMR) amongst bacterial pathogens, including methicillin resistant Staphylococcus aureus (MRSA). In recent publications, we have demonstrated a key role for a unique superoxide dismutase (SOD) metalloenzyme in this Gram-positive bacterium during infection of mammalian hosts. SODs detoxify the reactive oxygen species superoxide, to which pathogenic bacteria are exposed through the oxidative burst during colonisation of the host. This S. aureus-specific SOD, which can utilise either manganese or iron as a catalytic cofactor, is crucial in enabling a robust superoxide defence to be maintained during the host-imposed manganese starvation the bacterium experiences in vivo while colonising the host (https://doi.org/10.1371/journal.ppat.1006125).
We have determined X-ray crystal structures of this novel SOD enzyme and have performed detailed biochemistry to study its metal specificity (https://doi.org/10.1038/s41467-020-16478-0). Our data have demonstrated that this enzyme is crucial for S. aureus infection in mice, and that its three-dimensional structure is similar to, but its metal specificity is different from previously characterised SODs. Further mechanistic studies will thus determine how this unique enzyme functions, whereas drug discovery efforts have potential to develop a novel therapeutic strategy for combating this important community and nosocomial pathogen.
In this project, in collaboration with leading experts, we will use cutting-edge biophysical methods, including neutron diffraction (ND) and X-ray diffraction (XRD), nuclear magnetic resonance (NMR) spectrometry and electron paramagnetic resonance (EPR) spectroscopy, for high-resolution structural determination. We will utilise the structural data to determine the catalytic mechanism of this unusual SOD. We will initiate a structure-based drug design programme that will aim to identify novel inhibitors of its activity as potential lead compounds for anti-staphylococcal therapeutics and research tools. This project will thus enable both fundamental discoveries and underpin future drug discovery programs.
Working within a multi-disciplinary, collaborative research team, you will gain experience in biochemistry, structural biology, biophysics, and biological chemistry. You will express and purify recombinant proteins, including in specifically isotopically labelled forms, and gain expertise in biochemical assays, elemental analysis, protein crystallisation and biophysical analysis. You will gain skills in structure determination from X-ray and neutron diffraction data, analysis and interpretation of biophysics data, chemical synthesis of small-molecule inhibitors and medicinal chemistry, and in structure-based drug design and drug discovery protocols.
The supervisory team includes a biochemist with extensive experience in studying SOD enzymes (https://www.ncl.ac.uk/cbcb/staff/profile/kevinwaldron.html), a drug-discovery expert with extensive experience in both industry and academia (https://www.ncl.ac.uk/medical-sciences/research/research-themes/therapeutics/), and an experienced medicinal chemist (https://www.ncl.ac.uk/csbb/people/profile/ianhardcastle.html), who are already successfully collaborating on SOD-related projects. You will also work with our existing national and international collaborators to perform biophysical and microbiological studies. The successful student will therefore receive an exceptionally broad training in state-of-the-art methods in diverse skills for the modern academic or industrial research career.
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website: https://bit.ly/3lQXR8A
Studentships commence: 1st October 2021
Garcia et al. (2017) PLoS Pathogens 13: e1006125 (https://doi.org/10.1371/journal.ppat.1006125).
Hubbard et al. (2018) Methods in Molecular Biology 1732:1 (https://doi.org/10.1007/978-1-4939-7598-3_1).
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