01747nas a2200229   4500000000100000008004100001100001700042700001400059700001200073700001700085700001100102700001700113700001300130700001700143700001200160700001200172700001500184700001300199245013300212520115800345022001401503       2019                            d1 aWhitehouse A1 aThomas SE1 aBrown K1 aFanourakis A1 aChan D1 aLibardo DM J1 aMendes V1 aBoshoff HI M1 aFloto A1 aAbell C1 aBlundell T1 aCoyne AG00aDevelopment of inhibitors against Mycobacterium abscessus tRNA (m1G37) methyltransferase (TrmD) using fragment-based approaches.3 a<p>Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria (NTM) 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.</p>
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