Gene

Clofazimine

Respiratory chain

Mitochondrial respiratory chain

Leprosy

Biology

Mycobacterium tuberculosis

Oxidase test

Cytochrome c oxidase

Biochemistry

Drug

Immunology

Mutant

Drug development

Microbiology

Enzyme

Alternative oxidase

Tuberculosis

Mitochondrion

Pharmacology

Medicine

Pathology

Nature Communications

The viability of Mycobacterium tuberculosis ( Mtb ) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of Mtb -infected marmosets with a cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (Δ ndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δ ndh-2 mutant is only mildly attenuated in mice and not differently susceptible to clofazimine, a drug in clinical use proposed to engage NDH-2. These results demonstrate the intrinsic plasticity of Mtb ’s respiratory chain, and highlight the challenges associated with targeting the pathogen’s respiratory enzymes for tuberculosis drug development.

Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development