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 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.