Targeting aspartyl–tRNA synthetase as novel mode of action to fight Mycobacterium tuberculosis

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Duma, Bogdan Marian ORCID: https://orcid.org/0000-0003-2812-2387 (2019). Targeting aspartyl–tRNA synthetase as novel mode of action to fight Mycobacterium tuberculosis. University of Birmingham. Ph.D.

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Abstract

Tuberculosis is an infectious bacterial disease caused by Mycobacterium tuberculosis. Commonly affecting the lungs, tuberculosis has been ranked by the World Health Organization as a leading cause of death worldwide, causing 1.7 million fatalities in 2016 alone. Moreover, a daunting 10.4 million people are estimated to have been infected with tuberculosis in the same year.

To overcome this issue we have explored targeting aspartyl–tRNA syn- thetase an enzyme that to the best of our knowledge has not been researched so far against M. tuberculosis, as a possible target. Using an enzymatic assay developed in our research group combined with the results of a screening campaign performed using known tuberculosis inhibitors released by GSK as part of the GSK TB set, we have identified a novel class of compounds that target M. tuberculosis AspRS. This work contains the results of a structure– activity relationship study performed on this family of compounds as well as additional studies exploring the biological hit–enzyme interaction. These latter studies were performed attaching biotin and diazirine probes at specific positions of the initial hit. In addition, in the last chapter this work addi- tional molecular structures able to interact with and inhibit aspartyl–tRNA synthetase are evaluated.

Overall, although the structure–activity relationship study was inconclu- sive, the biotin probe employed in this work indicates that this was not because of the possible promiscuity of this family of compounds. Meanwhile, the ongoing analysis employing the diazirine probe is expected to help de- termine the binding mode of these compounds and the enzyme. This sets a path for the future exploration of this enzyme in targeting M. tuberculo- sis by either further exploring our initial family of compounds or through compounds coming out of new screening campaigns.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):