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

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 act...

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Autores principales: Abrahams, Katherine A., Batt, Sarah M., Gurcha, Sudagar S., Veerapen, Natacha, Bashiri, Ghader, Besra, Gurdyal S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10307805/
https://www.ncbi.nlm.nih.gov/pubmed/37380634
http://dx.doi.org/10.1038/s41467-023-39300-z
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author Abrahams, Katherine A.
Batt, Sarah M.
Gurcha, Sudagar S.
Veerapen, Natacha
Bashiri, Ghader
Besra, Gurdyal S.
author_facet Abrahams, Katherine A.
Batt, Sarah M.
Gurcha, Sudagar S.
Veerapen, Natacha
Bashiri, Ghader
Besra, Gurdyal S.
author_sort Abrahams, Katherine A.
collection PubMed
description 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.
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spelling pubmed-103078052023-06-30 DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid Abrahams, Katherine A. Batt, Sarah M. Gurcha, Sudagar S. Veerapen, Natacha Bashiri, Ghader Besra, Gurdyal S. Nat Commun Article 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. Nature Publishing Group UK 2023-06-28 /pmc/articles/PMC10307805/ /pubmed/37380634 http://dx.doi.org/10.1038/s41467-023-39300-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Abrahams, Katherine A.
Batt, Sarah M.
Gurcha, Sudagar S.
Veerapen, Natacha
Bashiri, Ghader
Besra, Gurdyal S.
DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
title DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
title_full DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
title_fullStr DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
title_full_unstemmed DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
title_short DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
title_sort dpre2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10307805/
https://www.ncbi.nlm.nih.gov/pubmed/37380634
http://dx.doi.org/10.1038/s41467-023-39300-z
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