Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site

Vitor Mendes (), Simon R. Green, Joanna C. Evans, Jeannine Hess, Michal Blaszczyk, Christina Spry, Owain Bryant, James Cory-Wright, Daniel S-H. Chan, Pedro H. M. Torres, Zhe Wang, Navid Nahiyaan, Sandra O’Neill, Sebastian Damerow, John Post, Tracy Bayliss, Sasha L. Lynch, Anthony G. Coyne, Peter C. Ray, Chris Abell, Kyu Y. Rhee, Helena I. M. Boshoff, Clifton E. Barry, Valerie Mizrahi, Paul G. Wyatt and Tom L. Blundell ()
Additional contact information
Vitor Mendes: University of Cambridge
Simon R. Green: University of Dundee
Joanna C. Evans: Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town
Jeannine Hess: University of Cambridge
Michal Blaszczyk: University of Cambridge
Christina Spry: University of Cambridge
Owain Bryant: University of Cambridge
James Cory-Wright: University of Cambridge
Daniel S-H. Chan: University of Cambridge
Pedro H. M. Torres: University of Cambridge
Zhe Wang: Weill Cornell Medical College
Navid Nahiyaan: Weill Cornell Medical College
Sandra O’Neill: University of Dundee
Sebastian Damerow: University of Dundee
John Post: University of Dundee
Tracy Bayliss: University of Dundee
Sasha L. Lynch: Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town
Anthony G. Coyne: University of Cambridge
Peter C. Ray: University of Dundee
Chris Abell: University of Cambridge
Kyu Y. Rhee: Weill Cornell Medical College
Helena I. M. Boshoff: National Institute of Allergy and Infectious Disease, National Institutes of Health
Clifton E. Barry: Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town
Valerie Mizrahi: Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town
Paul G. Wyatt: University of Dundee
Tom L. Blundell: University of Cambridge

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-20224-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20224-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-20224-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().