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J Med Chem. 2019 Aug 8;62(15):7210-7232. doi: 10.1021/acs.jmedchem.9b00809. Epub 2019 Jul 19.

Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches.

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Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , U.K.
Department of Biochemistry , University of Cambridge , Tennis Court Road , Cambridge CB2 1GA , U.K.
Molecular Immunity Unit, Department of Medicine, MRC Laboratory of Molecular Biology , University of Cambridge , Francis Crick Avenue, Cambridge Biomedical Campus , Cambridge CB2 0QH , U.K.
Cambridge Centre for Lung Infection , Royal Papworth Hospital , Cambridge CB23 3RE , U.K.
Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease , National Institutes of Health , 9000 Rockville Pike , Bethesda, Maryland 20892 , United States.


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.

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