The role of cytochrome bc1 inhibitors in future tuberculosis treatment regimens

Tuberculosis (TB) remains the foremost cause of death from infectious diseases globally, prompting ongoing efforts to improve treatment options. This includes developing compounds with novel modes of action and identifying optimal treatment regimens that allow for treatment shortening. One promising strategy involves targeting cytochrome bc<sub>1</sub> oxidase in Mycobacterium tuberculosis, a key enzyme in the respiratory chain. In this study, we evaluate the potential of cytochrome bc<sub>1</sub> inhibitors as partner drugs in TB combination regimens. Using a relapsing mouse model, we demonstrate that these inhibitors enhance regimen sterilisation and significantly reduce the time required for effective treatment. We also propose several novel combination strategies for both multidrug-resistant and drug-sensitive TB, where cytochrome bc<sub>1</sub> inhibitors contribute to sterilisation and improved treatment outcomes. Furthermore, M. tuberculosis clinical isolates exhibited heightened susceptibility to cytochrome bc<sub>1</sub> inhibitors compared to laboratory-adapted strains, highlighting the importance of using clinical isolates in TB drug discovery to better reflect the diversity of TB populations. These findings emphasise the potential of cytochrome bc<sub>1</sub> inhibition in the development of more effective and shorter treatment regimens for TB, supporting the need for further clinical investigation.

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Publication Details

Journal
Nature Communications
Published
2025-10-22
DOI
https://doi.org/10.1038/s41467-025-64427-6
Citations
1
Primary Topic
Tuberculosis Research and Epidemiology
Type
article
Field-Weighted Citation Impact
1.40

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article

The role of cytochrome bc1 inhibitors in future tuberculosis treatment regimens

Guillaume Golovkine, Gregory T. Robertson, Alexander S. Pym, Hannah Painter et al.
1 citations
Nature Communications
Tuberculosis Research and Epidemiology
1.40
article

The role of cytochrome bc1 inhibitors in future tuberculosis treatment regimens

Guillaume Golovkine, Gregory T. Robertson, Alexander S. Pym, Hannah Painter, Sarah N. P. Wong, Bart Stoops, Richard J. Wall, Marjolein Crabbe, Vivian Cox, Jérôme Guillemont, Jorge Esquivias, Anna M. Upton, Cristina Villellas, Nicole C. Ammerman, Lluís Ballell, Nicolas Véziris, Anne J. Lenaerts, Taane Gregory Clark, Eric L. Nuermberger, Anis Hassan, Nacer Lounis, Aurélie Chauffour, Katie Amssoms, Sylvie Sordello, Clara Aguilar-Pérez, Dirk A. Lamprecht, Veronica Gruppo, Alexandra Aubry, Jin‐Ho Choi, Kiyean Nam, John Dallow, Jeongjun Kim, Anil Koul, Thi Cuc, Laure Brock, José Manuel Bartolomé-Nebreda, Benny Baeten
article en
1 citations

Abstract

Tuberculosis (TB) remains the foremost cause of death from infectious diseases globally, prompting ongoing efforts to improve treatment options. This includes developing compounds with novel modes of action and identifying optimal treatment regimens that allow for treatment shortening. One promising strategy involves targeting cytochrome bc<sub>1</sub> oxidase in Mycobacterium tuberculosis, a key enzyme in the respiratory chain. In this study, we evaluate the potential of cytochrome bc<sub>1</sub> inhibitors as partner drugs in TB combination regimens. Using a relapsing mouse model, we demonstrate that these inhibitors enhance regimen sterilisation and significantly reduce the time required for effective treatment. We also propose several novel combination strategies for both multidrug-resistant and drug-sensitive TB, where cytochrome bc<sub>1</sub> inhibitors contribute to sterilisation and improved treatment outcomes. Furthermore, M. tuberculosis clinical isolates exhibited heightened susceptibility to cytochrome bc<sub>1</sub> inhibitors compared to laboratory-adapted strains, highlighting the importance of using clinical isolates in TB drug discovery to better reflect the diversity of TB populations. These findings emphasise the potential of cytochrome bc<sub>1</sub> inhibition in the development of more effective and shorter treatment regimens for TB, supporting the need for further clinical investigation.

Nature CommunicationsVol. 16(1)
Johnson & Johnson (United States) (US), Janssen (Belgium) (BE), Johns Hopkins University (US), Inserm (FR), University of Cape Town (ZA), Erasmus MC (NL), Sorbonne Université (FR), Janssen (France) (FR), London School of Hygiene & Tropical Medicine (GB), Assistance Publique – Hôpitaux de Paris (FR), Laboratoire National de Référence (MA), Janssen (United Kingdom) (GB), Centre d'Immunologie et des Maladies Infectieuses (FR), Qurient (South Korea) (KR), Johnson & Johnson (Brazil) (BR), Colorado State University (US), Evotec (United States) (US)
Colorado State University, Johns Hopkins University, European Federation of Pharmaceutical Industries and Associations, UK Research and Innovation, European Commission, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council
Openalex Percentile: Top 15%
Tuberculosis Research and Epidemiology
1.40
DOIOpen Access PDFOpenAlex
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