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Development of inhibitors against Mycobacterium abscessus tRNA (m 1 G37) methyltransferase (TrmD) using fragment-based approaches

DOI: 10.1021/acs.jmedchem.9b00809 DOI Help

Authors: Andrew J. Whitehouse (University of Cambridge) , Sherine E. Thomas (University of Cambridge) , Karen P. Brown (MRC Laboratory of Molecular Biology, University of Cambridge) , Alexander Fanourakis (University of Cambridge) , Daniel S.-h. Chan (University of Cambridge) , M. Daben J. Libardo (National Institutes of Health) , Vitor Mendes (University of Cambridge) , Helena I. M. Boshoff (National Institutes of Health) , R. Andres Floto (University of Cambridge; Royal Papworth Hospital) , Chris Abell (University of Cambridge) , Tom Blundell (University of Cambridge) , Anthony G. Coyne (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: July 2019
Diamond Proposal Number(s): 9537 , 14043 , 18548

Open Access Open Access

Abstract: Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.

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

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