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Mycobacterial energy metabolism currently attracts strong attention as new target space for development of anti-tuberculosis drugs. The imidazopyridine Q203 targets the cytochrome  bcc  complex of the respiratory chain, a key component in energy metabolism. Q203 blocks growth of  Mycobacterium tuberculosis  at nanomolar concentrations, however, it fails to actually kill the bacteria, which may limit the clinical applicability of this candidate drug. In this report we show that inhibition of cytochrome  bd , a parallel branch of the mycobacterial respiratory chain, by aurachin D invoked bactericidal activity of Q203. In biochemical assays using inverted membrane vesicles from  Mycobacterium tuberculosis  and  Mycobacterium smegmatis  we found that inhibition of respiratory chain activity by Q203 was incomplete, but could be enhanced by inactivation of cytochrome  bd , either by genetic knock-out or by inhibition with aurachin D. These results indicate that simultaneously targeting the cytochrome  bcc  and the cytochrome  bd  branch of the mycobacterial respiratory chain may turn out as effective strategy for combating  M. tuberculosis .

The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd