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

Abstract:

: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.

journal_name

Microb Pathog

journal_title

Microbial pathogenesis

authors

Rabha A,Singh A,Grover S,Kumari A,Pandey B,Grover A

doi

10.1016/j.micpath.2019.02.003

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

152-160

eissn

0882-4010

issn

1096-1208

pii

S0882-4010(18)31495-5

journal_volume

129

pub_type

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