Molecular dynamic assisted investigation on impact of mutations in deazaflavin dependent nitroreductase against pretomanid: a computational study.

In the past decade, TB drugs belonging to the nitroimidazole class, pretomanid and delamanid, have been authorised to treat MDR-TB and XDR-TB. With a novel inhibition mechanism and a reduction in the span of treatment, it is now being administered in various combinations. This approach is not the ultimate remedy since the target protein Deazaflavin dependent nitroreductase (Ddn) has a high mutation frequency, and already pretomanid resistant clinical isolates are reported in various studies. Ddn is essential for to emerge from hypoxia, and point mutations in critical residues confer resistance to Nitro-imidazoles. Among the pool of available mutants, we have selected seven mutants Ddn, Ddn, Ddn, Ddn, Ddn, Ddn, and Ddn, all of which exhibited resistance to pretomanid. To address this issue, through computational study primarily by MD simulation, we attempted to elucidate these point mutations' impact and investigate the resistance mechanism. Hence, the Ddn and mutant (MT) complexes were subjected to all-atom molecular dynamics (MD) simulations for 100 ns. Interestingly, we observed the escalation of the distance between cofactor and ligand in some mutants, along with a significant change in ligand conformation relative to the Ddn. Moreover, we confirmed that mutations rendered ligand instability and were ejected from the binding pocket as a result. In conclusion, the results obtained provide a new structural insight and vital clues for designing novel inhibitors to combat nitroimidazole resistanceCommunicated by Ramaswamy H. Sarma.