Supervisors: Dr Tim Blower and Professor Rick Lewis
Having graduated from Durham University in 2018 with a first-class degree in Biomedical Science I chose to stay on to complete a research masters under the supervision of Dr Tim Blower. The project focussed on promoter binding by type IV antitoxins of Mycobacterium tuberculosis characterising the protein-promoter interactions biochemically and attempting to solve the antitoxin structures using crystallography. I was awarded the MSc in 2019 following assessment by a thesis. I developed an interest in the toxin-antitoxin systems of Mycobacterium tuberculosis and how these may one day be used for drug-discovery. I enjoyed working on protein structures and complementing this with biochemical characterisations. Following my MSc I have stayed on under the supervision of Dr Tim Blower having accepted a DTP to study the type II parDE toxin -antitoxin systems of Mycobacterium tuberculosis.
Project Title: Untangling topoisomerase inhibition by parDE toxin-antitoxin systems of Mycrobacterium tuberculosis
My PhD project focusses on characterising the two parDE toxin-antitoxin systems present in the Mycobacterium tuberculosis H37Rv genome. The toxins of these systems, ParE1 and ParE2, are suspected to target the essential enzyme DNA gyrase. M. tuberculosis has evolved to carry DNA gyrase as its only topoisomerase. This enzyme is capable of relaxing positively supercoiled DNA, introducing negative supercoils in an ATP-dependent manner, and also decatenation. This has made DNA gyrase an attractive target for therapeutics and is indeed targeted by antibiotics such as fluoroquinolones, an important class of drugs in the treatment of tuberculosis. Resistance to mainline drugs, including fluoroquinolones, is emerging, therefore investigating alternative mechanisms of gyrase inhibition, such as via ParE toxins, may provide insights into drug-discovery. The goals of the project are to characterise the parDE systems showing they function as a toxin-antitoxin system in vivo, solve the structures of the parDE complexes via crystallography, and investigate the toxin-gyrase interactions both biochemically and structurally. Structural characterisation is planned to include a combination of crystallography and cryo-electron microscopy.
Gave a talk at the Federation of European Microbiological Societies conference 2019. The talk covered data on the type IV antitoxin-promoter interactions alongside structural characterisation and comparisons of type IV antitoxins.