Tuberculosis is a contagious bacterial ailment that primarily affects the lungs and is brought on by the bacterium Mycobacterium tuberculosis (MTB). An antimycobacterial medication called bedaquiline (BQ) is specified to treat multidrug-resistant tuberculosis (MDR-TB). Despite its contemporary use in clinical practice, the mutations (D32 A/G/N/V/P) constrain the potential of BQ by causing transitions in the structural conformation of the atpE subunit-c after binding. In this study, we have taken the benzylisoquinoline alkaloids from thalictrum foliolosum due to its antimicrobial activity reported in prior literature. We used an efficient and optimized structure-based strategy to examine the wild type (WT) and mutated protein upon molecule binding. Our results emphasize the drastic decline in BQ binding affinity of mutant and WT atpE subunit-c complexes compared to thalirugidine (top hit) from thalictrum foliolosum. The decrease in BQ binding free energy is due to electrostatic energy because nearly every atom in a macromolecule harbors a partial charge, and molecules taking part in molecular recognition will interact electrostatically. Similarly, the high potential mean force of thalirugidine than BQ in WT and mutant complexes demonstrated the remarkable ability to eradicate mycobacteria efficiently. Furthermore, the Alamar blue cell viability and ATP determination assay were performed to validate the computational outcomes in search of novel antimycobacterial. Upon closer examination of the ATP determination assay, it became apparent that both BQ and thalirugidine showed similar reductions in ATP levels at their respective MICs, presenting a potential common mechanism of action.
Keywords: Bedaquiline; MDR-TB; Thalictrum foliolosum; Thalirugidine; atpE.
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