Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. 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.

中文翻译：

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基于片段的新型靶向分支杆菌tRNA修饰的抑制剂的发现。

翻译移码错误通常对功能蛋白的合成有害，因此可以在治疗上促进其杀灭细菌。TrmD（tRNA-（N（1）G37）甲基转移酶）是细菌中必不可少的tRNA修饰酶，可防止蛋白质翻译过程中阅读框中的+1错误，并代表了开发新抗生素的潜在潜在目标。在这里，我们描述了基于结构指导的基于片段的药物发现方法在脓肿分枝杆菌中针对新型TrmD抑制剂设计的应用。片段文库的筛选，然后对命中进行结构指导的化学修饰，导致具有强大体外活性的药物样分子迅速发展TrmD抑制活性。这些化合物中的几种对浮游性脓肿支原体和结核分枝杆菌以及胞内脓肿支原体和麻风分枝杆菌均具有活性，表明它们有潜力作为新型广谱分枝杆菌药物的基础。