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; Gurdyal S. Besra

doi:10.1038/s41467-023-39300-z

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, Gurdyal S. Besra^*

^*Corresponding author for this work

Biosciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	3828
Number of pages	10
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-39300-z
Publication status	Published - 28 Jun 2023

Keywords

Antibiotics
Bacteria
Enzymes
Pathogens
Target identification

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-023-39300-zLicence: Creative Commons: Attribution (CC BY)

AbrahamsK2023DprE2Final published version, 1.18 MBLicence: Creative Commons: Attribution (CC BY)

1 Finished
1 Active

The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly, degradation and re-cycling pathways
Besra, D. (Principal Investigator), Bhatt, A. (Co-Investigator), Futterer, K. (Co-Investigator), Alderwick, L. (Co-Investigator) & Zhang, J. (Co-Investigator)
Medical Research Council
1/03/19 → 28/02/25
Project: Research Councils
MICA: Addressing the burgeoning problem of tuberculosis: Exploiting phenotypic hits to identify new protein targets for drug discovery
Besra, D. (Principal Investigator), Cox, L. (Co-Investigator) & Futterer, K. (Co-Investigator)
Medical Research Council
1/04/18 → 31/03/22
Project: Research Councils

Cite this

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title = "DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid",

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{\textquoteright}-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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T1 - DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid

AU - Abrahams, Katherine A.

AU - Batt, Sarah M.

AU - Gurcha, Sudagar S.

AU - Veerapen, Natacha

AU - Bashiri, Ghader

AU - Besra, Gurdyal S.

PY - 2023/6/28

Y1 - 2023/6/28

N2 - 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.

AB - 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.

KW - Antibiotics

KW - Bacteria

KW - Enzymes

KW - Pathogens

KW - Target identification

U2 - 10.1038/s41467-023-39300-z

DO - 10.1038/s41467-023-39300-z

M3 - Article

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SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3828

ER -

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

Abstract

Keywords

UN SDGs

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Projects

The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly, degradation and re-cycling pathways

MICA: Addressing the burgeoning problem of tuberculosis: Exploiting phenotypic hits to identify new protein targets for drug discovery

Cite this