MRC DiMeN Doctoral Training Partnership: Developing the next generation of glycopeptide antibiotics

The clinical deployment of antibiotics is undermined by antimicrobial resistance (AMR). Without new agents to treat antibiotic resistant bacterial infections, mortality rates are predicted to reach 10 million people per year by 2050. Most antibiotics are derived from natural products (NPs) produced by bacteria; however, this source was abandoned because of high rediscovery rates. However, we are amid a renaissance of NPs research fuelled by inexpensive access to genome sequencing and the development of sophisticated bioinformatic tools which have highlighted that most of the biosynthetic pathways for NPs are not expressed in the laboratory. If accessed, this biosynthetic ‘dark matter’ is widely believed to hold the key to a second Golden era of antibiotic discovery to combat AMR. 

We recently isolated and structurally characterised a novel glycopeptide antibiotic we named biffamycin. It possesses anti-mycobacterial and anti-staphylococcal bioactivity, including against vancomycin-resistant Staphylococcus aureus (VRSA). However, before this exciting new antibiotic can advance through the clinical pipeline, we must understand how it works and develop technology to produce new analogues.  

In this interdisciplinary project you will characterise the antibacterial mechanism of action for biffamycin. This information will be used to bioengineer the production of new biffamycin analogues with improved activity. Through the training offered by  this studentship you will become expert in cultivating various microorganisms and their genetic manipulation, protein production and purification, and biophysical techniques such as isothermal titration calorimetry, microscale thermophoresis and surface plasmon resonance. You will learn how to generate and analyse protein-biffamycin complexes using AlphaFold3, molecular docking, and structural biology techniques such as x-ray crystallography and nuclear magnetic resonance spectroscopy. These skills are essential to the next generation of bioscientist. You will also be further supported in acquiring transferable skills such as written and spoken communication, problem solving and critical thinking. This combination of skills and experience will make the successful candidate highly employable in both academia and industry. 

Lab websites: 

http://www.ryanseipkelab.com/ 

https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/411/dr-jennifer-tomlinson 

https://www.jic.ac.uk/people/barrie-wilkinson/ 

Benefits of being in the DiMeN DTP: 

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, York 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, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website: 

https://www.dimen.org.uk/