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

Katherine A. Abrahams, Sarah M. Batt, Sudagar S. Gurcha, Natacha Veerapen, Ghader Bashiri and Gurdyal S. Besra ()
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Katherine A. Abrahams: University of Birmingham
Sarah M. Batt: University of Birmingham
Sudagar S. Gurcha: University of Birmingham
Natacha Veerapen: University of Birmingham
Ghader Bashiri: University of Auckland
Gurdyal S. Besra: University of Birmingham

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39300-z

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