The role of cytochrome bc1 inhibitors in future tuberculosis treatment regimens

Clara Aguilar-Pérez (), Anne J. Lenaerts, Cristina Villellas, Jerome Guillemont, John Dallow, Hannah Painter, Nicole C. Ammerman, Anis Hassan, Guillaume Golovkine, Laure Brock, Sylvie Sordello, Aurélie Chauffour, Alexandra Aubry, Thi Cuc Mai, Sarah Wong, Taane G. Clark, Kiyean Nam, Jeongjun Kim, Jinho Choi, Marjolein Crabbe, Jorge Esquivias, Nacer Lounis, Bart Stoops, Katie Amssoms, Jose M. Bartolome-Nebreda, Veronica Gruppo, Gregory T. Robertson, Nicolas Veziris, Anna M. Upton, Eric L. Nuermberger, Vivian Cox, Lluis Ballell, Benny Baeten, Anil Koul, Alexander S. Pym, Richard J. Wall and Dirk A. Lamprecht ()
Additional contact information
Clara Aguilar-Pérez: Janssen Pharmaceutica NV
Anne J. Lenaerts: Colorado State University
Cristina Villellas: Janssen Pharmaceutica NV
Jerome Guillemont: Janssen-Cilag
John Dallow: London School of Hygiene and Tropical Medicine
Hannah Painter: London School of Hygiene and Tropical Medicine
Nicole C. Ammerman: Johns Hopkins University
Anis Hassan: London School of Hygiene and Tropical Medicine
Guillaume Golovkine: Route D’Espagne
Laure Brock: Route D’Espagne
Sylvie Sordello: Route D’Espagne
Aurélie Chauffour: Centre d’Immunologie et des Maladies Infectieuses
Alexandra Aubry: Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux
Thi Cuc Mai: Centre d’Immunologie et des Maladies Infectieuses
Sarah Wong: Centre d’Immunologie et des Maladies Infectieuses
Taane G. Clark: London School of Hygiene and Tropical Medicine
Kiyean Nam: Pangyo-ro
Jeongjun Kim: Pangyo-ro
Jinho Choi: Pangyo-ro
Marjolein Crabbe: Janssen Pharmaceutica NV
Jorge Esquivias: Janssen-Cilag SA a Johnson & Johnson company
Nacer Lounis: Janssen Pharmaceutica NV
Bart Stoops: Janssen Pharmaceutica NV
Katie Amssoms: Janssen Pharmaceutica NV
Jose M. Bartolome-Nebreda: Janssen-Cilag SA a Johnson & Johnson company
Veronica Gruppo: Colorado State University
Gregory T. Robertson: Colorado State University
Nicolas Veziris: Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux
Anna M. Upton: 303B College Road East
Eric L. Nuermberger: Johns Hopkins University
Vivian Cox: Johnson & Johnson Innovative Medicine
Lluis Ballell: Janssen-Cilag SA a Johnson & Johnson company
Benny Baeten: Janssen Pharmaceutica NV
Anil Koul: Janssen Pharmaceutica NV
Alexander S. Pym: Janssen Pharmaceutica
Richard J. Wall: London School of Hygiene and Tropical Medicine
Dirk A. Lamprecht: Janssen Pharmaceutica NV

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: 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 bc1 oxidase in Mycobacterium tuberculosis, a key enzyme in the respiratory chain. In this study, we evaluate the potential of cytochrome bc1 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 bc1 inhibitors contribute to sterilisation and improved treatment outcomes. Furthermore, M. tuberculosis clinical isolates exhibited heightened susceptibility to cytochrome bc1 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 bc1 inhibition in the development of more effective and shorter treatment regimens for TB, supporting the need for further clinical investigation.

Date: 2025
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DOI: 10.1038/s41467-025-64427-6

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