Development of Inhibitors against <i>Mycobacterium abscessus</i> tRNA (m<sup>1</sup>G37) Methyltransferase (TrmD) Using Fragment-Based Approaches.
Whitehouse AJ, Thomas SE, Brown KP, Fanourakis A, Chan DS, Libardo MDJ, Mendes V, Boshoff HIM, Floto RA, Abell C, Blundell TL, Coyne AG.
<i>Mycobacterium abscessus</i> (<i>Mab</i>) 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. <i>Mab</i> 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 (m<sup>1</sup>G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in <i>Mab</i> 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 <i>Mab</i> TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including <i>Mycobacterium tuberculosis</i> and <i>Mycobacterium leprae</i> in addition to <i>Mab</i>, supporting the use of TrmD as a target for the development of antimycobacterial compounds.