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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.<\/jats:p>","DOI":"10.1093\/nar\/gkaa539","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T15:11:34Z","timestamp":1592233894000},"page":"8099-8112","source":"Crossref","is-referenced-by-count":22,"title":["Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification"],"prefix":"10.1093","volume":"48","author":[{"given":"Sherine E","family":"Thomas","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK"}]},{"given":"Andrew J","family":"Whitehouse","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK"}]},{"given":"Karen","family":"Brown","sequence":"additional","affiliation":[{"name":"University of Cambridge Molecular Immunity Unit, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK"},{"name":"Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge CB2 0AY, UK"}]},{"given":"Sophie","family":"Burbaud","sequence":"additional","affiliation":[{"name":"University of Cambridge Molecular Immunity Unit, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK"}]},{"given":"Juan\u00a0M","family":"Belardinelli","sequence":"additional","affiliation":[{"name":"Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA"}]},{"given":"Jasper","family":"Sangen","sequence":"additional","affiliation":[{"name":"University of Cambridge Molecular Immunity Unit, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK"}]},{"given":"Ramanuj","family":"Lahiri","sequence":"additional","affiliation":[{"name":"National Hansen's Disease Program, Healthcare Systems Bureau, Health Resources and Services Administration, Department of Health and Human Services, Baton Rouge, LA, USA"}]},{"given":"Mark\u00a0Daben\u00a0J","family":"Libardo","sequence":"additional","affiliation":[{"name":"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"}]},{"given":"Pooja","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK"}]},{"given":"Sony","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Birkbeck College, University of London, Malet Street WC1E7HX, UK"}]},{"given":"Helena I M","family":"Boshoff","sequence":"additional","affiliation":[{"name":"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"}]},{"given":"Mary","family":"Jackson","sequence":"additional","affiliation":[{"name":"Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA"}]},{"given":"Chris","family":"Abell","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0205-5630","authenticated-orcid":false,"given":"Anthony\u00a0G","family":"Coyne","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK"}]},{"given":"Tom L","family":"Blundell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK"}]},{"given":"Rodrigo Andres","family":"Floto","sequence":"additional","affiliation":[{"name":"University of Cambridge Molecular Immunity Unit, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK"},{"name":"Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge CB2 0AY, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-2444","authenticated-orcid":false,"given":"V\u00edtor","family":"Mendes","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK"}]}],"member":"286","published-online":{"date-parts":[[2020,6,30]]},"reference":[{"key":"2020110412511250100_B1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S2213-2600(18)30057-2","article-title":"The global tuberculosis 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