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Mechanistic analysis elucidating the relationship between Lys96 mutation in Mycobacterium tuberculosis pyrazinamidase enzyme and pyrazinamide susceptibility

Chakshu Vats,J. Dhanjal,Sukriti Goyal,Ankita Gupta,N. Bharadvaja,A. Grover

Published 2015 in BMC Genomics

ABSTRACT

Background Pyrazinamide (PZA) is one of the most effective first line treatments against tuberculosis disease. The drug generally has bacteriostatic action. It also acts on bacterial spores which eliminates the chances of resurfacing of the infection. However, in recent years there has been a major increase in the occurrence of drug resistant bacterial strains. Resistance against PZA is caused by mutations in pyrazinamidase (PncA) protein which is the activator of the prodrug PZA. In the present study, we have tried to gain insights into the mechanism by which resistance develops due to K96R mutation occurring in the PncA catalytic region Results The binding cavity analysis showed an increase of 762.3 A 3 in the volume of the mutant protein. Docking studies revealed that PZA has a greater binding affinity for the native protein in comparison to the mutant protein. Molecular dynamics simulations further showed the role of flap region, which is present in PncA protein, in development of resistance to the drug. Conclusion The residues of flap region acquire more flexibility in mutant form of protein and thus move away from the active site. This leads to weak binding of the drug to the target residues which might interfere with the activation of the drug to functional form thereby giving rise to drug resistant bacterial strains. Background

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