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Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification

DOI: 10.1093/nar/gkaa539 DOI Help

Authors: Sherine E. Thomas (University of Cambridge) , Andrew J. Whitehouse (University of Cambridge) , Karen Brown (MRC Laboratory of Molecular Biology; Royal Papworth Hospital) , Sophie Burbaud (MRC Laboratory of Molecular Biology) , Juan m Belardinelli (Colorado State University) , Jasper Sangen (MRC Laboratory of Molecular Biology) , Ramanuj Lahiri (Department of Health and Human Services) , Mark daben j. Libardo (National Institute of Allergy and Infectious Disease, National Institutes of Health) , Pooja Gupta (University of Cambridge) , Sony Malhotra (Birkbeck College, University of London) , Helena I. M. Boshoff (National Institute of Allergy and Infectious Disease, National Institutes of Health) , Mary Jackson (Colorado State University) , Chris Abell (niversity of Cambridge) , Anthony g. Coyne (University of Cambridge) , Tom L. Blundell (University of Cambridge) , Rodrigo Andres Floto (MRC Laboratory of Molecular Biology; Royal Papworth Hospital) , Vitor Mendes (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nucleic Acids Research , VOL 6

State: Published (Approved)
Published: June 2020
Diamond Proposal Number(s): 9537 , 14043 , 18548

Open Access Open Access

Abstract: Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs.

Journal Keywords: Nucleic acid modification; Targeted inhibition of gene function

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 10/08/2020 11:44

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gkaa539.pdf

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)