Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2023-05-13 , DOI: 10.1016/j.bmcl.2023.129331
Andrew J Wilkinson 1 , Nicola Ooi 1 , Jonathan Finlayson 1 , Victoria E Lee 1 , David Lyth 1 , Kathryn S Maskew 1 , Rebecca Newman 1 , David Orr 1 , Keith Ansell 2 , Kristian Birchall 2 , Peter Canning 2 , Peter Coombs 2 , Lucia Fusani 2 , Ed McIver 2 , João Pisco 2 , Philip M Ireland 3 , Christopher Jenkins 3 , Isobel H Norville 3 , Stephanie J Southern 3 , Richard Cowan 4 , Gareth Hall 4 , Catherine Kettleborough 2 , Victoria J Savage 1 , Ian R Cooper 1
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The post-transcriptional modifier tRNA-(N1G37) methyltransferase (TrmD) has been proposed to be essential for growth in many Gram-negative and Gram-positive pathogens, however previously reported inhibitors show only weak antibacterial activity. In this work, optimisation of fragment hits resulted in compounds with low nanomolar TrmD inhibition incorporating features designed to enhance bacterial permeability and covering a range of physicochemical space. The resulting lack of significant antibacterial activity suggests that whilst TrmD is highly ligandable, its essentiality and druggability are called into question.
中文翻译：
通过一系列有效的 TrmD 抑制剂的设计和微生物学分析，评估潜在抗菌靶点 TrmD 的成药性
转录后修饰剂 tRNA-(N 1 G37) 甲基转移酶 (TrmD) 已被提出对许多革兰氏阴性和革兰氏阳性病原体的生长至关重要，但先前报道的抑制剂仅显示出较弱的抗菌活性。在这项工作中，片段命中的优化导致具有低纳摩尔 TrmD 抑制的化合物结合了旨在增强细菌渗透性和覆盖一系列物理化学空间的特征。由此导致的显着抗菌活性的缺乏表明，虽然 TrmD 具有高度配体性，但其必要性和成药性受到质疑。
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