Mechanistic Principles Behind Molecular Mechanism of Rifampicin Resistance in Mutant RNA Polymerase Beta Subunit of Mycobacterium tuberculosis. Issue 12 (9th June 2017)

• Record Type: Journal Article
• Authors: Singh, Aditi; Grover, Sonam; Sinha, Siddharth; Das, Mriganko; Somvanshi, Pallavi; Grover, Abhinav
• Is Part Of: Journal of cellular biochemistry. Volume 118:Issue 12(2017)
• Page Start: 4594
• Page End: 4606
• Publication Date: 2017-06-09
• Subjects: TB -- RIFAMPICIN -- RpoB -- MECHANISM -- RESISTANCE -- TUBERCULOSIS; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.26124
• Languages: English
• ISSNs: 0730-2312

Abstract

ABSTRACT: Evolution of drug‐resistant Mycobacterium strains threatens the TB treatment and control programs globally. Rifampicin (RIF) is an important first line antitubercular drug. Resistance to Rifampicin is caused mainly by mutations in its target RNA polymerase beta subunit protein (RpoB). RpoB contains a Rifampicin resistance determining region (RRDR) and has several potent sites for mutations. In this study, we have investigated mutations of a single site (H451) to eight different amino acids, involved in RIF resistance. Long‐term molecular dynamics simulations were performed on wild type (WT) and mutant protein structures and various structural analysis were carried out to elucidate the dynamic behavior of WT and mutant forms. Essential dynamics uncovered the difference in conformational flexibility and collective modes of motions between WT and mutants. MMPBSA calculations and interaction pattern analysis revealed the binding site relocation in some mutants. This study presents an exhaustive analysis of RIF binding to the WT and mutant RpoB and clearly highlights structural mechanism for differences in stable binding of Rifampicin with WT than the mutant targets. J. Cell. Biochem. 118: 4594–4606, 2017. © 2017 Wiley Periodicals, Inc. Abstract : Resistance to Rifampicin (RIF) is caused mainly by mutations in its target RNA polymerase beta subunit protein (RpoB). In this study, we have investigated mutations of a single site (H451) to eight different amino acids, involved in RIF resistance. This study presents an exhaustive analysis of RIF binding to the WT and mutant RpoB and clearly highlights structural mechanism for differences in stable binding of Rifampicin with WT than the mutant targets.