Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence

Significance Tuberculosis drug development remains crucial for countering the spread of drug resistance worldwide. New susceptibilities in metabolic pathways must be identified to find novel drugs to eradicate tuberculosis. The electron transport chain (ETC) is the target of recently developed tuberculosis drugs. To assess whether the NADH dehydrogenases of the ETC would be potential drug candidates, we deleted the genes encoding the three Mycobacterium tuberculosis NADH dehydrogenases Nuo, Ndh, and NdhA. We found that although the NADH dehydrogenases were not essential for growth individually, deletion of both nuo and ndh had the most profound effect on Mycobacterium tuberculosis viability and virulence. We propose that screening compound libraries against both Ndh and Nuo will lead to promising drug candidates to fight tuberculosis.