8apt
Crystal Structure of H. influenzae TrmD in complex with Compound 13Crystal Structure of H. influenzae TrmD in complex with Compound 13
Structural highlights
FunctionTRMD_HAEIG Specifically methylates guanosine-37 in various tRNAs. Publication Abstract from PubMedThe post-transcriptional modifier tRNA-(N(1)G37) 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. Evaluating the druggability of TrmD, a potential antibacterial target, through design and microbiological profiling of a series of potent TrmD inhibitors.,Wilkinson AJ, Ooi N, Finlayson J, Lee VE, Lyth D, Maskew KS, Newman R, Orr D, Ansell K, Birchall K, Canning P, Coombs P, Fusani L, McIver E, Pisco J, Ireland PM, Jenkins C, Norville IH, Southern SJ, Cowan R, Hall G, Kettleborough C, Savage VJ, Cooper IR Bioorg Med Chem Lett. 2023 Jun 15;90:129331. doi: 10.1016/j.bmcl.2023.129331. , Epub 2023 May 13. PMID:37187252[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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