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DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid.

Katherine A AbrahamsSarah M BattSudagar S GurchaNatacha VeerapenGhader BashiriGurdyal S Besra
Published in: Nature communications (2023)
Mycobacterium tuberculosis is one of the global leading causes of death due to a single infectious agent. Pretomanid and delamanid are new antitubercular agents that have progressed through the drug discovery pipeline. These compounds are bicyclic nitroimidazoles that act as pro-drugs, requiring activation by a mycobacterial enzyme; however, the precise mechanisms of action of the active metabolite(s) are unclear. Here, we identify a molecular target of activated pretomanid and delamanid: the DprE2 subunit of decaprenylphosphoribose-2'-epimerase, an enzyme required for the synthesis of cell wall arabinogalactan. We also provide evidence for an NAD-adduct as the active metabolite of pretomanid. Our results highlight DprE2 as a potential antimycobacterial target and provide a foundation for future exploration into the active metabolites and clinical development of pretomanid and delamanid.
Keyphrases
  • mycobacterium tuberculosis
  • drug discovery
  • cell wall
  • ms ms
  • pulmonary tuberculosis
  • current status
  • single molecule
  • risk assessment
  • human health