2. Academic Validation
  3. Remission spectroscopy resolves the mechanism of action of bedaquiline within living mycobacteria

Remission spectroscopy resolves the mechanism of action of bedaquiline within living mycobacteria

  • Nat Commun. 2025 Nov 25;16(1):11018. doi: 10.1038/s41467-025-65928-0.
Suzanna H Harrison # 1 2,  Rowan C Walters # 1 2,  Chen-Yi Cheung 3,  Roger J Springett 1 2 4,  Gregory M Cook 3 5,  Morwan M Osman # 6 7,  James N Blaza 8 9
Affiliations

Affiliations

  • 1 York Structural Biology Laboratory, Department of Chemistry, University of York, York, UK.
  • 2 York Biomedical Research Institute, University of York, York, UK.
  • 3 Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
  • 4 Cellspex Ltd, Northamptonshire, UK.
  • 5 School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
  • 6 York Structural Biology Laboratory, Department of Chemistry, University of York, York, UK. [email protected].
  • 7 York Biomedical Research Institute, University of York, York, UK. [email protected].
  • 8 York Structural Biology Laboratory, Department of Chemistry, University of York, York, UK. [email protected].
  • 9 York Biomedical Research Institute, University of York, York, UK. [email protected].
  • # Contributed equally.
PMID: 41290674 DOI: 10.1038/s41467-025-65928-0
Abstract

Bedaquiline, an ATP Synthase Inhibitor, is the spearhead of transformative therapies against drug-resistant Mycobacterium tuberculosis. Here, we use remission spectroscopy to measure the energy-transducing cytochromes within unperturbed, respiring suspensions of mycobacterial and human cells, allowing spectroscopic measurements of electron transport chains as they power living cells and respond to bedaquiline. No evidence is found for protonophoric or ionophoric uncoupling. Rather, by directly inhibiting ATP Synthase, bedaquiline slows the respiratory supercomplex (Qcr:Cta; bcc:aa3) by increasing the proton-motive force, causing sub-second redirection of electron flux through the cytochrome bd oxidase (CydAB) to O2. Electron flux redirection explains the idiosyncratic bedaquiline-induced increase in O2 consumption rates previously observed. Redirection occurs as CydAB is present even in cells grown in plentiful O2. Applying the same approach to human cells did not detect bedaquiline-induced inhibition of mitochondrial function despite such inhibition being seen in isolated systems. Overall, we clarify how bedaquiline works, why different models for its action developed, and the mechanisms underlying the synergy of bedaquiline in combination regimes.

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