Insights into the use of cytochrome bc1 inhibitors for future therapeutic strategies for tuberculosis

Recent efforts to improve tuberculosis (TB) treatment options have focused on developing molecules with novel mechanisms of action and identifying optimal treatment regimens. Inhibition of Mycobacterium tuberculosis cytochrome bc1 oxidase has emerged as a promising therapeutic target that could potentially contribute to improved TB combination regimens. Using a relapsing mouse model, we demonstrate that cytochrome bc1 inhibitors could serve as effective partner drugs, enhancing regimen sterilisation. We propose several novel regimen strategies for both multidrug-resistant TB (MDR-TB) and drug-sensitive TB (DS-TB), where cytochrome bc1 inhibitors contribute to sterilisation and treatment shortening. Additionally, we show that clinical isolates exhibit heightened susceptibility to cytochrome bc1 inhibitors compared to laboratory-adapted strains, further supporting their translational potential. These findings suggest that cytochrome bc1 inhibitors have significant potential to improve TB treatment outcomes and highlight the need for further studies to evaluate their clinical contribution to novel treatment regimens.