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Peer-reviewedCC BY 4.0Antimicrobial Agents and Chemotherapy

Inhibition of type II NADH dehydrogenase in Mycobacterium tuberculosis reveals collateral vulnerability in the electron transport chain

  • Vien Q. T. Ho1
  • Vincent Fontaine2
  • Ernesto Anoz-Carbonell1
  • Kamel Djaout1
  • Clement Vigier3
  • Leo Faion3
  • Samsher Singh4
  • Sushovan Dam1
  • Jonathan Chatagnon1
  • Stéphanie Slupek1
  • Rudy Antoine1
  • Aurélie Chauffour2
8 more authors
  • Alexandra Aubry2,5
  • Benoit Deprez3
  • Kevin Pethe4,6,7
  • Nicolas Veziris2,5
  • Nicolas Willand3
  • Robert Jansen8
  • Baptiste Villemagne3
  • Ruben C. Hartkoorn1
8 affiliations
  1. 1University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017, Center for Infection and Immunity of Lille (CIIL), Lille, France
  2. 2Centre d'Immunologie et des Maladies Infectieuses, CIMI, Sorbonne Université, CNRS, Inserm, Paris, France
  3. 3University Lille, Inserm, Institut Pasteur de Lille, U1177-Drugs and Molecules for Living Systems, Lille, France
  4. 4Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
  5. 5Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, AP-HP, Sorbonne Université, Paris, France
  6. 6Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore, Singapore
  7. 7National Center for Infectious Diseases (NCID), Singapore, Singapore
  8. 8Radboud Institute for Biological and Environmental Sciences, Radboud University, Nijmegen, the Netherlands
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Abstract

To sustain the anti-tuberculosis drug development pipeline, novel antibiotics must be developed both as standalone agents and as components of future combination regimens. To this end, tricyclic-spirolactams (TriSLa)-based inhibitors of mycobacterial type II NADH dehydrogenase (Ndh-2) represent a promising novel class of antibiotics, though activity is carbon source dependent. Initial studies established an enhanced understanding of the impact of TriSLa on mycobacteria using metabolomics and transcriptomics. Then, CRISPRi chemical-genetics and extensive in vitro TriSLa-combination studies showed that Ndh-2 inhibition resulted in rendering other components of the electron transport chain vulnerable, even in conditions when TriSLa was inactive alone. Finally, identified in vitro synergistic TriSLa-antibiotic combinations were validated to also give modestly improved in vivo efficacy. Together, this work expands our understanding of how Ndh-2 inhibition impacts bacterial physiology and reveals how it sensitizes the bacterium to electron transport chain inhibitors, providing a foundation for future TriSLa-based combination regimens.

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Cite

BibTeXRIS
BibTeX
@article{ho2026inhibition,
  title = {{Inhibition of type II NADH dehydrogenase in Mycobacterium tuberculosis reveals collateral vulnerability in the electron transport chain}},
  author = {Vien Q. T. Ho and Vincent Fontaine and Ernesto Anoz-Carbonell and Kamel Djaout and Clement Vigier and Leo Faion and Samsher Singh and Sushovan Dam and Jonathan Chatagnon and Stéphanie Slupek and Rudy Antoine and Aurélie Chauffour and Alexandra Aubry and Benoit Deprez and Kevin Pethe and Nicolas Veziris and Nicolas Willand and Robert Jansen and Baptiste Villemagne and Ruben C. Hartkoorn},
  journal = {Antimicrobial Agents and Chemotherapy},
  year = {2026},
  month = sep,
  doi = {10.1128/aac.00756-26},
  url = {https://hal.science/hal-05780392v1},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Inhibition of type II NADH dehydrogenase in Mycobacterium tuberculosis reveals collateral vulnerability in the electron transport chain
AU  - Vien Q. T. Ho
AU  - Vincent Fontaine
AU  - Ernesto Anoz-Carbonell
AU  - Kamel Djaout
AU  - Clement Vigier
AU  - Leo Faion
AU  - Samsher Singh
AU  - Sushovan Dam
AU  - Jonathan Chatagnon
AU  - Stéphanie Slupek
AU  - Rudy Antoine
AU  - Aurélie Chauffour
AU  - Alexandra Aubry
AU  - Benoit Deprez
AU  - Kevin Pethe
AU  - Nicolas Veziris
AU  - Nicolas Willand
AU  - Robert Jansen
AU  - Baptiste Villemagne
AU  - Ruben C. Hartkoorn
PY  - 2026
DA  - 2026/09/24
JO  - Antimicrobial Agents and Chemotherapy
DO  - 10.1128/aac.00756-26
UR  - https://hal.science/hal-05780392v1
AB  - To sustain the anti-tuberculosis drug development pipeline, novel antibiotics must be developed both as standalone agents and as components of future combination regimens. To this end, tricyclic-spirolactams (TriSLa)-based inhibitors of mycobacterial type II NADH dehydrogenase (Ndh-2) represent a promising novel class of antibiotics, though activity is carbon source dependent. Initial studies established an enhanced understanding of the impact of TriSLa on mycobacteria using metabolomics and transcriptomics. Then, CRISPRi chemical-genetics and extensive in vitro TriSLa-combination studies showed that Ndh-2 inhibition resulted in rendering other components of the electron transport chain vulnerable, even in conditions when TriSLa was inactive alone. Finally, identified in vitro synergistic TriSLa-antibiotic combinations were validated to also give modestly improved in vivo efficacy. Together, this work expands our understanding of how Ndh-2 inhibition impacts bacterial physiology and reveals how it sensitizes the bacterium to electron transport chain inhibitors, providing a foundation for future TriSLa-based combination regimens.
SN  - 0066-4804
SN  - 1098-6596
ER  -