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https://hdl.handle.net/10356/146983
Title: | Targeting the bacterial epitranscriptome for antibiotic development : discovery of novel tRNA-(N1G37) methyltransferase (TrmD) inhibitors | Authors: | Zhong, Wenhe Koay, Ann Ngo, Anna Li, Yan Nah, Qianhui Wong, Yee Hwa Chionh, Yok Hian Ng, Hui Qi Koh-Stenta, Xiaoying Poulsen, Anders Foo, Klement McBee, Megan Choong, Meng Ling El Sahili, Abbas Kang, Congbao Matter, Alex Lescar, Julien Hill, Jeffrey Dedon, Peter |
Keywords: | Science::Biological sciences | Issue Date: | 2019 | Source: | Zhong, W., Koay, A., Ngo, A., Li, Y., Nah, Q., Wong, Y. H., Chionh, Y. H., Ng, H. Q., Koh-Stenta, X., Poulsen, A., Foo, K., McBee, M., Choong, M. L., El Sahili, A., Kang, C., Matter, A., Lescar, J., Hill, J. & Dedon, P. (2019). Targeting the bacterial epitranscriptome for antibiotic development : discovery of novel tRNA-(N1G37) methyltransferase (TrmD) inhibitors. ACS Infectious Diseases, 5(3), 326-335. https://dx.doi.org/10.1021/acsinfecdis.8b00275 | Project: | ING137070-BIO RG154/14 MOE2015- T2-2-075 |
Journal: | ACS Infectious Diseases | Abstract: | Bacterial tRNA modification synthesis pathways are critical to cell survival under stress and thus represent ideal mechanism-based targets for antibiotic development. One such target is the tRNA-(N1G37) methyltransferase (TrmD), which is conserved and essential in many bacterial pathogens. Here we developed and applied a widely applicable, radioactivity-free, bioluminescence-based high-throughput screen (HTS) against 116350 compounds from structurally diverse small-molecule libraries to identify inhibitors of Pseudomonas aeruginosa TrmD ( PaTrmD). Of 285 compounds passing primary and secondary screens, a total of 61 TrmD inhibitors comprised of more than 12 different chemical scaffolds were identified, all showing submicromolar to low micromolar enzyme inhibitor constants, with binding affinity confirmed by thermal stability and surface plasmon resonance. S-Adenosyl-l-methionine (SAM) competition assays suggested that compounds in the pyridine-pyrazole-piperidine scaffold were substrate SAM-competitive inhibitors. This was confirmed in structural studies, with nuclear magnetic resonance analysis and crystal structures of PaTrmD showing pyridine-pyrazole-piperidine compounds bound in the SAM-binding pocket. Five hits showed cellular activities against Gram-positive bacteria, including mycobacteria, while one compound, a SAM-noncompetitive inhibitor, exhibited broad-spectrum antibacterial activity. The results of this HTS expand the repertoire of TrmD-inhibiting molecular scaffolds that show promise for antibiotic development. | URI: | https://hdl.handle.net/10356/146983 | ISSN: | 2373-8227 | DOI: | 10.1021/acsinfecdis.8b00275 | Schools: | School of Biological Sciences | Research Centres: | NTU Institute of Structural Biology Singapore-MIT Alliance for Research and Technology |
Rights: | © 2019 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. | Fulltext Permission: | open | Fulltext Availability: | With Fulltext |
Appears in Collections: | SBS Journal Articles |
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Targeting the Bacterial Epitranscriptome for Antibiotic Development_ Discovery of Novel tRNA-(N1G37) Methyltransferase (TrmD) Inhibitors PV.pdf | 3.52 MB | Adobe PDF | View/Open |
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