Synthetic lethality of Mycobacterium tuberculosis NADH dehydrogenases is due to impaired NADH oxidation.

Importance: In 2022, it was estimated that 10.6 million people fell ill, and 1.6 million people died from tuberculosis (TB). Available treatment is lengthy and requires a multi-drug regimen, which calls for new strategies to cure Mycobacterium tuberculosis ( Mtb ) infections more efficiently. We have previously shown that simultaneous inactivation of type 1 (Ndh-1) and type 2 (Ndh-2) NADH dehydrogenases kills Mtb . NADH dehydrogenases play two main physiological roles: NADH oxidation and electron entry into the respiratory chain. Here, we show that this bactericidal effect is a consequence of impaired NADH oxidation. Importantly, we demonstrate that Ndh-1/Ndh-2 synthetic lethality can be achieved through simultaneous chemical inhibition, which could be exploited by TB drug development programs.
Competing Interests: The authors declare no conflict of interest.