Investigating the impacts of resistance mutations in Mycobacterium tuberculosis in order to improve the selection of new drug targets

Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis (M. tb). There is an urgent need to understand the mechanism by which the mutations confer resistance in order to design new drugs to reduce its emergence in the future. The present study involves analyses of drug-resistant mutations in M. tb using both computational and experimental approaches. In Chapter 2 in-silico analyses of mutations linked to isoniazid (INH) and rifampicin (RIF) resistance were performed in seven proteins. These proteins included the catalase-peroxidase (KatG), Enoyl-Acyl Carrier Protein reductase (InhA), β-ketoacyl ACP synthase (KasA), alkyl hydroxide reductase (AhpC) and NADH dehydrogenase (Ndh) for INH resistance and RpoB and RpoC for RIF resistance. The impacts of mutations on the structure and function of these proteins were predicted using software developed in the Blundell group, including impacts on stability using SDM, a statistical approach, and mCSM, a machine learning approach, while the effects of mutations on protein-protein interactions and protein-ligand affinity were predicted using mCSM-PPI and mCSM-lig ... (continues)