FST19: Novel inhibitor of isocitrate lyase as a potent antitubercular agent against mycobacterium tuberculosis

Among bacteria diseases, tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is still a major cause of death in humans. One major obstacle with current TB chemotherapy is the lack of an effective, simple treatment. New anti-TB drugs that shorten the duration of TB chemotherapy are urgently needed. Few mutations attenuate (Mtb) more profoundly than deletion of its isocitrate lyase (ICL). We have previously shown that knocking-out Mtb’s ICL leads to multiplicity of metabolic defects from perturbation of the methylcitrate cycle (MCC), a major propionate metabolic pathway. Consequently, ICL is an important anti-TB drug target. However, there are still no druggable ICL inhibitors.

Mtb ICL has been cloned and crystallised. We have produced synthetic variants of methylisocitrate, the substrate of ICL, that are designed to inhibit ICL catalytic activity. This project will express and purify Mtb ICL and study the effect of the inhibitors on its catalytic activity. The binding of the most potent compounds to ICL will then be studied by crystallography. This data will enable us to refine essential contacts in the active site by inform design of further, more potent inhibitors. Compounds with significant in vitro activity against Mtb ICL will then be evaluated against the whole bacterium in collaboration with the University of Southern California.

The student will receive training in relevant techniques/technologies and gain expertise in a number of key project planning and analytical research and subject specific skills. The student will also take part in the University Graduate School and Faculty Doctoral Research Development Programme (DRDP) including transferable skills (eg presentation skills, scientific writing and employability skills) which aid in their future career progression. The student will also be encouraged to join relevant learned societies, which provide excellent support for students in terms of training opportunities and meetings to disseminate and publish their research.

Further enquiries

Please contact Dr Saki Raheem, [email protected] and Dr Mark Odell, [email protected].

Deadline

5pm on 10 February 2017

Apply now

Applications should be made to the Life Sciences MPhil/PhD programme and you should clearly state that you are applying for a Quintin Hogg Trust Scholarship and the Scholarship code (eg FST1) on your application.

Full details on how to apply.

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