Insights into the Mechanisms of the Pyrazinamide Resistance of Three Pyrazinamidase Mutants N11K, P69T, and D126N

• DOI: 10.1021/acs.jcim.8b00525
• Publication Date: 2018-11-27T21:46:57Z
• Authors: Muhammad Junaid; Muhammad Tahir Khan; Shaukat Iqbal Malik; Dong-Qing Wei
• Keywords: Pyrazinamide; Docking (animal)

In an effort to discover the mechanism of resistance offered by Mycobacterium tuberculosis (Mtb) toward pyrazinamide (PZA) drug, extensive molecular dynamics strategy was employed. PZA is a first-line prodrug that effectively cuts therapy time 33% (from 9 6 months). Pyrazinamidase enzyme (PZase), encoded pncA gene, responsible for activation into pyrazinoic acid (POA). POA toxic and potently inhibits growth latent Mtb even at low pH values. caused three genes pncA, rpsA, panD. Among them, gene contributes 72–99% resistance. Hence, present study focused on novel mutations N11K, P69T, D126N in gene. study, possible these studied through simulation docking techniques. Our in-depth analysis results are strong agreement with our experimental observation. The binding pocket showed decrease volume active site hinder correct orientation drug site. Moreover, Patchdock score found be as compared WT showing disturbance shape complementarity between PZase drug. These were disturb position Fe2+ ion. mutations, allosterically disturbed MMGBSA analyses affinity conclusion, result weak also cause significant structural deformations lead This provides useful information other than parts may protein folding ligand displacement effects, altering biological functions.