title: Molecular principles behind pyrazinamide resistance due to mutations in panD gene in Mycobacterium tuberculosis.
abstract: The latest resurrection of drug resistance poses serious threat to the treatment and control of the disease. Mutations have been detected in panD gene in the Mycobacterium tuberculosis (Mtb) strains. Mutation of histidine to arginine at residue 21 (H21R) and isoleucine to valine at residue 29 (I49V) in the non-active site of panD gene has led to PZA resistance. This study will help in reconnoitering the mechanism of pyrazinamide (PZA) resistance caused due to double mutation identified in the panD gene of M. tuberculosis clinical isolates. It is known that panD gene encodes aspartate decarboxylase essential for β-alanine synthesis that makes it a potential therapeutic drug target for tuberculosis treatment. The knowledge about the molecular mechanism conferring drug resistance in M. tuberculosis is scarce, which is a significant challenge in designing successful therapeutic drug. In this study, structural and dynamic repercussions of H21R-I49V double mutation in panD complexed with PZA have been corroborated through docking and molecular dynamics based simulation. The double mutant (DM) shows low docking score and thus, low binding affinity for PZA as compared to the native protein. It was observed that the mutant protein exhibits more structural fluctuation at the ligand binding site in comparison to the native type. Furthermore, the flexibility and compactness analyses indicate that the double mutation influence interaction of PZA with the protein. The hydrogen-bond interaction patterns further supported our results. The covariance and PCA analysis elucidated that the double mutation affects the collective motion of residues in phase space. The results have been presented with an explanation for the induced drug resistance conferred by the H21R-I49V double mutation in panD gene and gain valuable insight to facilitate the advent of efficient therapeutics for combating resistance against PZA.
authors.affiliation: Department of Biotechnology, Panjab University, Chandigarh 160014, India.
authors.forename: Bharati
authors.initials: B
authors.lastname: Pandey
authors.affiliation: Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi 110016, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Grover
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Chetna
authors.initials: C
authors.lastname: Tyagi
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk 304022, Rajasthan, India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk 304022, Rajasthan, India.
authors.forename: Salma
authors.initials: S
authors.lastname: Jamal
authors.affiliation: Department of Biotechnology, TERI University, Vasant Kunj, New Delhi 110070, India.
authors.forename: Aditi
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Biotechnology, Panjab University, Chandigarh 160014, India.
authors.forename: Jagdeep
authors.initials: J
authors.lastname: Kaur
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address: abhinavgr@gmail.com.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005798:Genes, Bacterial; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D025341:Principal Component Analysis; D011487:Protein Conformation; D011718:Pyrazinamide / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D008024:Ligands; D011718:Pyrazinamide
keywords: Docking; Pyrazinamide; RMSD; RMSF; Simulation