Due to its emerging resistance to first-line anti-TB medications, tuberculosis (TB) is one of the most contagious illness in the world. According to reports, the effectiveness of treating TB is severely impacted by drug resistance, notably resistance caused by mutations in the pncA gene-encoded pyrazinamidase (PZase) to the front-line drug pyrazinamide (PZA). The present study focused on investigating the resistance mechanism caused by the mutations D12N, T47A, and H137R to better understand the structural and molecular events responsible for the resistance acquired by the pncA gene of Mycobacterium tuberculosis (MTB) at the structural level. Bioinformatics analysis predicted that all three mutations were deleterious and located near the active centre of the pncA, affecting its functional activity. Furthermore, molecular dynamics simulation (MDS) results established that mutations significantly reduced the structural stability and caused the rearrangement of FE2+ in the active centre of pncA. Moreover, essential dynamics analysis, including principal component analysis (PCA) and free energy landscape (FEL), concluded variations in the protein motion and decreased conformational space in the mutants. Additionally, the mutations potentially impacted the network topologies and altered the residual communications in the network. The complex simulation study results established the significant movement of the flap region from the active centre of mutant complexes, further supporting the flap region's significance in developing resistance to the PZA drug. This study advances our knowledge of the primary cause of the mechanism of PZA resistance and the structural dynamics of pncA mutants, which will help us to design new and potent chemical scaffolds to treat drug-resistant TB (DR-TB).
Keywords: Molecular dynamics simulation; Mutation; PCA based FEL analysis; PncA; Residue interaction network.
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