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Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development
- Source :
- Nature Communications, Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019)
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group UK, 2019.
-
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.<br />New tuberculosis therapies, targeting respiratory chain components of Mycobacterium tuberculosis, are under development. Here the authors show that, contrary to common belief, some of these components are not essential for pathogen viability and/or virulence in animal models of infection.
- Subjects :
- 0301 basic medicine
Pyridines
Mutant
Respiratory chain
Antitubercular Agents
General Physics and Astronomy
Clofazimine
Electron Transport Complex III
Mice
Piperidines
Bacterial genetics
lcsh:Science
Lung
Oxidase test
Multidisciplinary
biology
NADH dehydrogenase
Imidazoles
Callithrix
Adaptation, Physiological
3. Good health
Drug development
Gene Knockdown Techniques
Antibacterial drug resistance
Pathogens
medicine.drug
Tuberculosis
Science
030106 microbiology
In Vitro Techniques
General Biochemistry, Genetics and Molecular Biology
Article
Microbiology
Target validation
Mycobacterium tuberculosis
Electron Transport
Electron Transport Complex IV
03 medical and health sciences
Drug Development
medicine
Animals
Tuberculosis, Pulmonary
NADH Dehydrogenase
General Chemistry
biology.organism_classification
medicine.disease
030104 developmental biology
biology.protein
lcsh:Q
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....0d1cbea81cfc2ede413244ba2f106dfa