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Synergistic Interplay of The Co-administration of Rifampin And Newly Developed Anti-TB Drug: Could It Be a Promising New Line of TB Therapy?

[ Vol. 21 , Issue. 6 ]

Author(s):

Clement Agoni, Pritika Ramharack and Mahmoud E.S. Soliman*   Pages 453 - 460 ( 8 )

Abstract:


Background: Rifampin resistance has dampened the existing efforts being made to control the global crisis of Tuberculosis and antimicrobial resistance in general. Previous studies that attempted to provide insights into the structural mechanism of Rifampin resistance did not utilize the X-ray crystal structure of Mycobacterium tuberculosis RNA polymerase due to its unavailability.

Methods/Results: We provide an atomistic mechanism of Rifampin resistance in a single active site mutating Mycobacterium tuberculosis RNA polymerase, using a recently resolved crystal structure. We also unravel the structural interplay of this mutation upon co-binding of Rifampin with a novel inhibitor, D-AAP1. Mutation distorted the overall conformational landscape of Mycobacterium tuberculosis RNA polymerase, reduced binding affinity of Rifampin and shifted the overall residue interaction network of the enzyme upon binding of only Rifampin. Interestingly, co-binding with DAAP1, though impacted by the mutation, exhibited improved Rifampin binding interactions amidst a distorted residue interaction network.

Conclusion: Findings offer vital conformational dynamics and structural mechanisms of mutant enzyme-single ligand and mutant enzyme-dual ligand interactions which could potentially shift the current therapeutic protocol of Tuberculosis infections.

Keywords:

Mycobacterium tuberculosis, RNA polymerase, co-inhibition, Rifampin resistance, TB therapy, Rifampin.

Affiliation:

Molecular Bio-computation and Drug Design Research Laboratory, School of Health Sciences, University of KwaZulu- Natal, Westville Campus, Durban 4001, Molecular Bio-computation and Drug Design Research Laboratory, School of Health Sciences, University of KwaZulu- Natal, Westville Campus, Durban 4001, Molecular Bio-computation and Drug Design Research Laboratory, School of Health Sciences, University of KwaZulu- Natal, Westville Campus, Durban 4001



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