Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.

Autor:	Mendes V; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK. vgm23@cam.ac.uk., Green SR; Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK., Evans JC; MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of Excellence for Biomedical TB Research & Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa., Hess J; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Blaszczyk M; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK., Spry C; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Bryant O; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK., Cory-Wright J; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK., Chan DS; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Torres PHM; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK., Wang Z; Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA., Nahiyaan N; Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA., O'Neill S; Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK., Damerow S; Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK., Post J; Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK., Bayliss T; Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK., Lynch SL; MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of Excellence for Biomedical TB Research & Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa., Coyne AG; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Ray PC; Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK., Abell C; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Rhee KY; Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA., Boshoff HIM; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA., Barry CE 3rd; MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of Excellence for Biomedical TB Research & Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa.; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA., Mizrahi V; MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of Excellence for Biomedical TB Research & Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa., Wyatt PG; Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK., Blundell TL; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK. tom@cryst.bioc.cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2021 Jan 08; Vol. 12 (1), pp. 143. Date of Electronic Publication: 2021 Jan 08.
DOI:	10.1038/s41467-020-20224-x
Abstrakt:	Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.
Databáze:	MEDLINE
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