The recent discovery of small molecules targeting the cytochrome : in triggered interest in the terminal respiratory oxidases for antituberculosis drug development. The mycobacterial cytochrome : consists of a menaquinone:cytochrome reductase ( ) and a cytochrome -type oxidase. The clinical-stage drug candidate Q203 interferes with the function of the subunit b of the menaquinone:cytochrome reductase. Despite the affinity of Q203 for the : complex, the drug is only bacteriostatic and does not kill drug-tolerant persisters. This raises the possibility that the alternate terminal -type oxidase (cytochrome oxidase) is capable of maintaining a membrane potential and menaquinol oxidation in the presence of Q203. Here, we show that the electron flow through the cytochrome oxidase is sufficient to maintain respiration and ATP synthesis at a level high enough to protect from Q203-induced bacterial death. Upon genetic deletion of the cytochrome oxidase-encoding genes , Q203 inhibited mycobacterial respiration completely, became bactericidal, killed drug-tolerant mycobacterial persisters, and rapidly cleared infection in vivo. These results indicate a synthetic lethal interaction between the two terminal respiratory oxidases that can be exploited for anti-TB drug development. Our findings should be considered in the clinical development of drugs targeting the cytochrome : , as well as for the development of a drug combination targeting oxidative phosphorylation in .