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DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
- Source :
- Nature Communications, Vol 14, Iss 1, Pp 1-10 (2023)
- Publication Year :
- 2023
- Publisher :
- Nature Portfolio, 2023.
-
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.
- Subjects :
- Science
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 14
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.40bdd0a34d744b8786bc6a3db7dc1740
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41467-023-39300-z