Targeting biosynthetic and regulatory pathways of Mycobacterium tuberculosis as novel drug targets.
Applications are invited from Graduates in Microbiology and Pharmacy at Master’s level to the Mycobacterial Drug Discovery group within the School of Medicine, Pharmacy and Health. The PhD programme will centre on Mycobacterium tuberculosis, the causative agent of tuberculosis, which latently infects one third of the world’s population. Its capacity to do this can be attributed to its unique cell envelope and its vast array of regulatory systems. The emergence of drug resistant M. tuberculosis to current antibacterial therapies is of great concern to healthcare worldwide. The development and discovery of the next generation of antibacterial therapeutic agents is paramount to controlling the world incidence of tuberculosis.
The project will identify key biosynthetic and regulatory enzymes via the creation of conditional knockouts and biochemical characterisation. M. tuberculosis has a vast array of enzymes functioning in the complex pathways essential for the synthesis of components of the cell wall whether in vivo or ex vivo. The deletion of these genes will provide basic information regarding their putative activity in relation to their cell wall-related biosynthesis functions and their role in macrophage survivability. The initial investigation will be by phenotypic analyses after modification of the genome of M. tuberculosis. The associated regulatory systems will be investigated to understand the underpinning biology of these stress response regulators in Mycobacterial survivability. Crystallographic analysis of purified recombinant protein will enable molecular modelling and pharmacophore design to be performed. The medicinal chemistry platform based upon Property based Fragment Design principals will utilise these models to synthesis a library of potential anti-mycobacterial agents. This multidisciplinary interaction between microbiology, molecular biology, crystallography and pharmacology will engage collaborations within the Division of Pharmacy and the Department of Chemistry. Potential candidates will require a strong background in microbiological techniques and protein purification; chemical synthesis background would be advantageous.
Successful candidates will be encouraged to participate in national and international conferences on antibacterial resistance and Mycobacterium biology. The project/candidate will be actively involved Wolfson Special Interest Group “Filling the Void – the search for new antimicrobial targets and inhibitors” (https://www.dur.ac.uk/wolfson.institute/sig/void/).
For information about the project please contact Dr Alistair Brown [email protected]
To find out if you are eligible to apply for a place on a PhD programme please contact [email protected]