Effect of mutations on the structure of Mycobacterium tuberculosis KatG protein and interactions with Isoniazid - An in-silico study

Fight against tuberculosis (TB) is still ongoing in India. The problem of drug resistance in Mycobacterium tuberculosis (M.tb) has obligated the need of studying key enzymes involved in drug interaction. One of the known M.tb enzyme targets for the primary drug isoniazid is catalase-peroxidase (KatG). In this study, we induced mutations (observed in clinical samples) at specific locations around the catalytic binding site of KatG protein and elucidated the impact of these mutations on the protein structural stability, secondary structure deformation and binding interaction with the drug ligand. It is clear from this study that mutations near the heme region have impacted the structure of the protein and the binding pattern with the drug. It can be hypothesized that this change leads to inhibition of KatG protein catalase and free radical generation activity. This could impact the KatG-Isoniazid interaction and overall make the bacteria resistant to the drug.