The PhD project will focus on the development and characterisation of new inhibitors of bacterial RNA polymerase (RNAP) for the treatment of infectious diseases, including drug resistant tuberculosis (TB).
Bacterial RNAP is a central enzyme of the bacterial cell and is a validated drug target for the development of antibiotics, some currently used against deadliest bacterial infections. The rifamycins (e.g. rifampicin) are semisynthetic antibiotics that inhibit bacterial RNAP by sterically blocking RNA extension and are key to treating the leading cause of death by bacterial infectious disease – TB. However, the emergence of RIF-resistance, through RNAP mutation, is a major problem in TB treatment which has to be overcome.
The project will involve an integrated medicinal chemistry/molecular biology approach, to overcoming RIF-resistance through the study of novel RIF-RNAP interactions and to develop improved RIF related RNAP inhibitors.
Previous work by the Newcastle team resulted in the discovery of novel RIF-related natural products, the kanglemycins, as potent inhibitors of RIF-resistant RNAP (Moll Cell (2018) 72:263 and unpublished). This project will continue our RNAP drug discovery program to develop semi-synthetic RIFs as drug-like kanglemycin mimics, through the use of computation guided rational molecular design and molecular/structural biology.
The PhD student will gain experience working across both chemistry and molecular biology laboratories to achieve an integrated development of novel RNAP inhibitors. The student will undertake a parallel computational and laboratory study to design and synthesize new rifamycin derivatives. Evaluation of these molecules will involve microbiological, molecular and structural (CryoEM and crystallography) biology studies, resulting in an iterative design loop, with lead compounds tested against resistant TB.
This project will provide training in both modern structurally led computational drug design as well as in laboratory based synthetic chemistry, biochemistry, molecular biology, microbiology and structural biology. Through working with the supervisory team and other group members, the student will gain an excellent knowledge of the modern interdisciplinary sciences and collaboration skills needed to thrive in the modern research world.
Prof Zenkin: https://www.ncl.ac.uk/cbcb/staff/profile/nikolayzenkin.html
Dr Hall: https://www.ncl.ac.uk/nes/people/profile/michaelhall.html
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, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog
Further information on the programme and how to apply can be found on our website:
https://www.dimen.org.uk/how-to-apply
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