Significance of catalase-peroxidase (KatG) mutations in mediating isoniazid resistance in clinical strains of Mycobacterium tuberculosis .

Unissa, A.N.; Doss, C.G.P.; Kumar, T.; Sukumar, S.; Lakshmi, A.R.; Hanna, L.E .

Journal of Global Antimicrobial Resistance; 2018; 15: 111-120.

Abstract: O bjectives: Isoniazid (INH) is still the most important first-line antitubercular drug. INH resistance is regarded as a major impediment to the tuberculosis (TB) control programme and contributes to the emergence of multidrug-resistant strains. Mutation at position 315 in the katG gene, encoding the catalase-peroxidase (KatG) enzyme, is the major cause of INH resistance in Mycobacterium tuberculosis . Therefore, investigation of the molecular mechanisms of INH resistance is the need of the hour.


M ethods : To understand the clinical importance of KatG mutants (MTs) leading to INH resistance, in this study five MTs (S315T, S315I, S315R, S315N and S315G) were modelled, docked and interacted with INH in dynamic state.


R esults : The binding affinity based on docking was found to be higher for MTs than for wild-type (WT) isolates, except for MT-S315R, indicating rigid binding of INH with MT proteins compared with the flexible binding seen in the WT. Analysis of molecular dynamics (MD) experiments suggested that fluctuations and deviations were higher at the INH binding residues for MTs than for the WT. Reduction in the hydrogen bond network after MD in all KatG enzymes implies an increase in the flexibility and stability of protein structures. Superimposition of MTs upon the WT structure showed a significant deviation that varies for the different MTs.


C onclusions : It can be inferred that the five KatG MTs affect enzyme activity in different ways, which could be attributed to conformational changes in MT KatG that result in altered binding affinity to INH and eventually to INH resistance.


Keywords: Mycobacterium tuberculosis ; Isoniazid resistance; INH; KatG; S315 mutations; Molecular modelling


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