Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification
| Autor: | Sony Malhotra, Helena I. Boshoff, Tom L. Blundell, Ramanuj Lahiri, Pooja Gupta, Anthony G. Coyne, Karen Brown, Vitor Mendes, Mary Jackson, M. Daben J. Libardo, R. Andres Floto, Andrew J. Whitehouse, Chris Abell, Juan Manuel Belardinelli, Sherine E. Thomas |
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| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Translational frameshift TRNA modification Methyltransferase biology 030306 microbiology Chemistry Drug discovery Mycobacterium abscessus biology.organism_classification 3. Good health Mycobacterium tuberculosis 03 medical and health sciences Enzyme Biochemistry Mycobacterium leprae 030304 developmental biology |
| DOI: | 10.1101/564013 |
| Popis: | Translational frameshift errors are often deleterious to the synthesis of functional proteins as they lead to the production of truncated or inactive proteins. 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 has been identified as a therapeutic target for several bacterial infections. Here we validate TrmD as a target inMycobacterium abscessusand describe the application of a structure-guided fragment-based drug discovery approach for the design of a new class of inhibitors against this enzyme. A fragment library screening followed by structure-guided chemical elaboration of hits led to the development of compounds with potentin vitroTrmD inhibitory activity. Several of these compounds exhibit activity against planktonicM. abscessus and Mycobacterium tuberculosis.The compounds were further active in macrophage infection models againstMycobacterium lepraeandM. abscessussuggesting the potential for novel broad-spectrum mycobacterial drugs. |
| Databáze: | OpenAIRE |
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