Structural basis for isoniazid resistance in KatG double mutants of Mycobacterium tuberculosis.

Structural basis for isoniazid resistance in KatG double mutants of Mycobacterium tuberculosis.

Publication date: Feb 04, 2019

The failure of drugs for effective treatment against infectious diseases can be attributed to resistant forms of causative agents. The evasive nature of Mycobacterium tuberculosis is partly associated to its physical features, such as having a thick cell wall and incorporation of beneficial mutations leading to drug resistance. The pro drug Isoniazid (INH) interacts with an enzyme catalase peroxidase to get converted into its active form and upon activation stops the cell wall synthesis thus killing the Mycobacterium. The most common mutation i.e. S315T leads to high degree of drug resistance by virtue of its position in the active site. Here, we have characterized the prominent attributes of two double mutant isolates S315 T/D194G and S315T/M624V which are multi drug resistant and extremely drug resistant, respectively. Protein models were generated using the crystal structure which were then subjected to energy minimization and long term molecular dynamics simulations. Further, computational analysis showed decreasing ability of INH binding to the mutants in order of: Native > S315T/D194G > S315T/M624V. Also, a trend was observed that as the docking score and binding area decreased, there was a significant increase in the distortion of the 3D geometry of the mutants as observed by PCA analysis.

Rabha, A., Singh, A., Grover, S., Kumari, A., Pandey, B., and Grover, A. Structural basis for isoniazid resistance in KatG double mutants of Mycobacterium tuberculosis. 04744. 2019 Microb Pathog.



Please signin to view all article content and metadata.


Leave a Comment

Your email address will not be published. Required fields are marked *