S. aureus has been a leading cause of healthcare- and community-associated infections worldwide, with a number of patients infected with methicillin-resistant S. aureus (MRSA). MRSA encompasses strains resistant to most antibiotics in clinical use. In addition to its impact on health, MRSA infections impose a significant economic burden due to higher costs and more severe side effects associated with vancomycin, longer hospital stays, and potential long-lasting disability. Furthermore, few new drugs have entered the market in the past decade, and they are chemical analogues of existing ones against which resistance rapidly emerges. Thus the development of novel antibiotics with novel mechanisms of action against MRSA is urgently needed. The detailed characterisation of novel molecular targets is a paramount step to speed up the drug discovery pipeline.
This project focuses on the enzymology of an exceptionally promising, yet underexplored, tRNA methyltransferase: m1A22-tRNA methyltransferase (TrmK). TrmK catalyses the transfer of a methyl group from SAM to the N1 of adenine on position 22 of several tRNAs, yielding m1A22-tRNA and SAH. TrmK was found to be essential for S. aureus survival in growth medium and during infection. Moreover, TrmK has no homologues in mammals, which bodes well for target selectivity of inhibitors.
A PhD student will use molecular biology, biochemistry and single-molecule biophysics approaches to determine the substrate specificity of TrmK for various tRNAs; establish the role of the C-terminal domain in catalysis; uncover the effect of the m1A22 modification in tRNA; obtain the crystal structure of TrmK bound to tRNA.
You will master skills in site-directed mutagenesis, heterologous gene expression, protein purification, enzyme kinetics and mathematical data modelling, tRNA synthesis and biophysics, protein crystallography, chemical labelling of proteins, and single-molecule microscopy. These are highly sought-after skills in both academia and industry. The student will present their results in group meetings and internal departmental seminars, and at scientific conferences. The student will also benefit from the array of technique-focused and transferable skills training offered through Eastbio and St Andrews GradSkills.
The successful candidate will have a 1st-class honours BSc and/or an MSc in Chemistry or Biochemistry, research experience, and enthusiasm for elucidating enzyme mechanisms. Candidates should contact Dr da Silva and/or Prof Penedo-Esteiro to discuss their application and perspective on the project.
HOW TO APPLY
Application instructions can be found on the EASTBIO website- http://www.eastscotbiodtp.ac.uk/how-apply-0
1) Download and complete the Equality, Diversity and Inclusion survey.
2) Download and complete the EASTBIO Application Form.
3) Submit an application to St Andrews University through the Online Application Portal
Your online application must include the following documents:
- Completed EASTBIO application form
- 2 References (to be completed on the EASTBIO Reference Form, also found on the EASTBIO website)
- Academic Qualifications
- English Language Qualification (if applicable)
Unfortunately due to workload constraints, we cannot consider incomplete applications. Please make sure your application is complete by Monday 5th December 2022.
Queries on the project can be directed to the project supervisor.
Queries on the application process can be directed to Jess Fitzgerald at [Email Address Removed]
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