Please use this identifier to cite or link to this item: 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
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

SCOPUSTM   
Citations 20

20
Updated on Jan 25, 2023

Web of ScienceTM
Citations 20

20
Updated on Jan 26, 2023

Page view(s)

195
Updated on Jan 28, 2023

Download(s) 50

55
Updated on Jan 28, 2023

Google ScholarTM

Check

Altmetric


Plumx

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.