Drug resistance mechanism of PncA inMycobacterium tuberculosis

Abstract

Tuberculosis continues to be a global health threat. Pyrazinamide (PZA) is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to PZA represents an important public health problem, as both first- and second-line treatment regimens include PZA. It becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by the bacterial pyrazinamidase (PncA) enzyme. Resistance to PZA is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are involved in resistance towards PZA. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three-dimensional (3D) conformational behaviour of native and mutants PncA. Our analysis clearly indicates that the mutation (D8G, S104R and C138Y) in PncA is responsible for rigid binding cavity which in turn abolishes conversion of PZA to its active form and is the sole reason for PZA resistance. Excessive hydrogen bonding between PZA binding cavity residues and their neighbouring residues are the reason of rigid binding cavity during simulation. We present an exhaustive analysis of the binding site flexibility and its 3D conformations that may serve as new starting points for structure-based drug design and helps the researchers to design new inhibitors with consideration of rigid criterion of binding residues due to mutation of this essential target. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:11.

Multicenter Study of the Emergence and Genetic Characteristics of Pyrazinamide-Resistant Tuberculosis in China

“…Mutations or variations in pncA leading to the loss of PZase activity is the major mechanism leading to PZA resistance (3). However, while high numbers of PZA-resistant cases can be related to inactivation of the PZase, the genetic variants, including single nucleotide polymorphisms (SNPs) and small deletions, are highly diverse and scattered over the full length of the 561-bp pncA gene (4,5). This complicates the development of molecular tests, as no "hot spot region" comprising the majority of mutations is observed in the pncA gene.…”

In-silico screening of cancer associated mutation on PLK1 protein and its structural consequences

“…In our study we used Polyphen 2.0 [29], SIFT [30], Imutant 3.0 [31], PANTHER [32], PhD-SNP [33], SNP&GO [34], MutPred [35] and Dr Cancer [36] to prioritize the most deleterious and disease-associated nsSNPs from the available SNP datasets obtained from swissprot/Uniprot database. Conformational changes in the 3D structure of the protein accounts for its time dependent physiological affinities and various biochemical pathway alterations [37][38][39][40][41][42]. Molecular docking and molecular dynamics simulation (MDS) approach was applied to examine, how the predicted mutation (W414F) affect the interaction between Plk1 PBD and their target peptides which is sufficient to inhibit the over expression of plk1.…”

Structure-Function Correlation Analysis of Connexin50 Missense Mutations Causing Congenital Cataract: Electrostatic Potential Alteration Could Determine Intracellular Trafficking Fate of Mutants

“…Currently in silico approach has emerged as a powerful tool to explore biological systems. Molecular dynamics simulation studies have provided valuable structural insights into the pathomechanism of various diseases and even drug resistance mechanisms of different microorganisms [5–14]. As the crystal structure of human Cx50 is not yet resolved in atomic resolution we pursued our studies on a homology model of human Cx50.…”