Investigating novel drug targets and the biosynthetic pathways of lipids in mycobacteria

[摘要] The spread of the tuberculosis (TB) has been further accelerated by the emergence of multi- and extensively-drug resistant Mycobacterium tuberculosis strains, thereby further increasing the need to characterise novel drug targets and develop anti-TB agents. The cell wall of M. tuberculosis plays a key role in survival of the pathogen in the host cell, making it an attractive drug target. The findings in this thesis present three different studies that contribute to the discovery of novel drug targets. Using a whole-cell screening approach and the generation of spontaneous drug-resistant mutants in M. smegmatis, a surrogate model of M. tuberculosis, we identified a new inhibitor which targets glycerol metabolism. The two remaining studies involved studying the biosynthetic pathways of critical cell-wall components. In this first study, Conditional expression specialised transduction essentiality test was used to confirm the essentiality of MSMEG3859 in M. smegmatis, an enzyme which generates mannose donors that are utilised in the biosynthesis of higher order Phosphatidyl-myo-inositol mannosides, Lipomannan (LM) and Lipoarabinomannan (LAM), important immunomodulators in mycobacteria. Furthermore, a deletion mutant of Protein kinase H (PknH) in M. tuberculosis was used to demonstrate its importance in the production of LM/LAM and Phthiocerol dimycoserosates, a glycolipid that is also involved in TB pathogenesis. Thus, both Ppm1 and PknH can potentially be used as future therapeutic targets against M. tuberculosis.

[发布机构] University:University of Birmingham;Department:School of Chemistry

[关键词] Q Science;QD Chemistry