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

Autor: Abrahams KA; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Batt SM; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Gurcha SS; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Veerapen N; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK., Bashiri G; Laboratory of Molecular and Microbial Biochemistry, School of Biological Sciences, University of Auckland, 3A Symonds Street, Auckland, 1010, New Zealand., Besra GS; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. g.besra@bham.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Jun 28; Vol. 14 (1), pp. 3828. Date of Electronic Publication: 2023 Jun 28.
DOI: 10.1038/s41467-023-39300-z
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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