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Remission cytochrome spectroscopy reveals the mode of action of bedaquiline in living mycobacteria

S H Harrison(1) R C Walters(1) M M Osman(1) R J Springett(1,3) G M Cook(2) J N Blaza(1)

1:University of York; 2:Queensland University of Technology; 3:CellSpex

The ATP synthase inhibitor Bedaquiline (BDQ) is the cornerstone of new regimens that have accelerated the treatment multidrug-resistant tuberculosis. Despite its clear importance, its precise bactericidal mechanism continues to debated: specifically whether BDQ binding to ATP synthase disrupts the proton motive force by inducing a leaky ‘uncoupled’ state, or simply blocks catalysis.  To unravel its mechanism of action we applied non-invasive methods to study the effects of BDQ on the oxidative phosphorylation system in live mycobacteria. Via the use of a specialised bioenergetic chamber we are able to monitor changes in cytochrome oxidation states through multi-wavelength remission spectroscopy while measuring the oxygen consumption rate of cells in real time. We find that BDQ’s effects do not match those of established uncouplers/ionophores that disrupt the proton motive force. Our results demonstrate BDQ acts as a direct inhibitor of ATP synthase and its effects on oxygen consumption are the result of electrons being routed through cytochrome bd oxidase. This strategy by the bacteria limits their susceptibility to back pressure and highlights bd oxidase as a key target for future combination therapies to increase the effectiveness of BDQ.

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