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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Katherine A. Abrahams & Sarah M. Batt & Sudagar S. Gurcha & Natacha Veerapen & Ghader Bashiri & Gurdyal S. Besra, 2023. "DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39300-z
    DOI: 10.1038/s41467-023-39300-z
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    1. C. Kendall Stover & Paul Warrener & Donald R. VanDevanter & David R. Sherman & Taraq M. Arain & Michael H. Langhorne & Scott W. Anderson & J. Andrew Towell & Ying Yuan & David N. McMurray & Barry N. K, 2000. "A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis," Nature, Nature, vol. 405(6789), pages 962-966, June.
    2. Kaj M. Kreutzfeldt & Robert S. Jansen & Travis E. Hartman & Alexandre Gouzy & Ruojun Wang & Inna V. Krieger & Matthew D. Zimmerman & Martin Gengenbacher & Jansy P. Sarathy & Min Xie & Véronique Dartoi, 2022. "CinA mediates multidrug tolerance in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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