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

Autor: Beites T; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA., O'Brien K; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA., Tiwari D; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA., Engelhart CA; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA., Walters S; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA.; School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia., Andrews J; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, 20892, USA., Yang HJ; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, 20892, USA., Sutphen ML; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, 20892, USA., Weiner DM; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, 20892, USA., Dayao EK; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, 20892, USA., Zimmerman M; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA., Prideaux B; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA., Desai PV; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Masquelin T; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Via LE; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, 20892, USA.; Institute of Infectious Disease and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town, 7925, South Africa., Dartois V; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA., Boshoff HI; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, 20892, USA., Barry CE 3rd; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, 20892, USA.; Institute of Infectious Disease and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town, 7925, South Africa., Ehrt S; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA., Schnappinger D; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA. dis2003@med.cornell.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Oct 31; Vol. 10 (1), pp. 4970. Date of Electronic Publication: 2019 Oct 31.
DOI: 10.1038/s41467-019-12956-2
Abstrakt: 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.
Databáze: MEDLINE