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

Abstract

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 (Δndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δndh-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.

Host immunity increases Mycobacterium tuberculosis reliance on cytochrome bd oxidase

“…(14). Conversely, other studies have concluded that the cytochrome bd oxidase is dispensable for growth in C57BL/6J and BALB/C mice (2,4). We suspect that these differing conclusions were caused by variations in the infection models.…”

“…Most notably is Q203 (Telacebec) which is currently in clinical trials (5). However, the flexibility of the mycobacterial respiratory chain has raised concerns about the potential efficacy of this drug (2,4,35). One strategy to enhance the efficacy of respiratory inhibition is to simultaneously target both the bc 1 /aa 3 and bd oxidase complexes, which produces a bactericidal effect (4,6,9).…”

“…These terminal oxidases transfer electrons from the ETC to O 2 and contribute to the proton motive force (PMF) gradient that powers the production of ATP by ATP synthase. In Mtb, cytochrome bc 1 /aa 3 is required for optimal growth and persistence in macrophage and infection mouse models using both genetic (2) and chemical inhibition of the complex (3)(4)(5).…”

“…While it is plausible that these properties contribute to Mtb fitness during infection, the role played by the cytochrome bd oxidase in the mouse model of TB remains unclear. Some studies report no effect of cydABDC mutation, while others describe a fitness defect at the later stages of infection (2,4,14). Thus, while it is clear that the cytochrome bd oxidase is active in mycobacteria, the non-redundant role of this system during infection is unknown.…”

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

“…Detailed gene-deletion and gene-silencing studies of nuo, ndh, and ndhA performed by Vilcheze et al, established that individually, none of the NADH dehydrogenases are essential in vitro or in vivo [34]. Beites et al further demonstrated that NDH-2 enzymes are jointly essential for growth in the presence of long-chain fatty acids, but are dispensable for growth on some carbon sources such as glycerol [35]. Moreover, a strain deficient for NDH-2 activity is only mildly attenuated in mice [35].…”