Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N¹)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism
Name
acs.jmedchem.9b00582.pdf
Description
Published version
Size
5.5 MB
Format
Adobe PDF
Checksum (MD5)
04ed1d6ef8ce4e44e4588f7d91145560
Author(s)
Zhong, Wenhe
Pasunooti, Kalyan Kumar
Balamkundu, Seetharamsing
Wong, Yee Hwa
Nah, Qianhui
Gadi, Vinod
Gnanakalai, Shanmugavel
Chionh, Yok Hian
McBee, Megan E.
Gopal, Pooja
Date Issued
August 2019
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Citation
Zhong, Wenhe et al. "Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N¹)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism." Journal of Medicinal Chemistry 62, 17 (August 2019): 7788-7805 © 2019 American Chemical Society
Version
Final published version
Abstract
Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N1G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa and Mycobacterium tuberculosis, we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding. This tyrosine-flipping mechanism is uniquely found in P. aeruginosa TrmD and renders the enzyme inaccessible to the cofactor S-adenosyl-l-methionine (SAM) and probably to the substrate tRNA. Biophysical and biochemical structure-activity relationship studies provided insights into the mechanisms underlying the potency of thienopyrimidinones as TrmD inhibitors, with several derivatives found to be active against Gram-positive and mycobacterial pathogens. These results lay a foundation for further development of TrmD inhibitors as antimicrobial agents.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1021/acs.jmedchem.9b00582
