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
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.