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Title: Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism
Authors: Zhong, Wenhe
Pasunooti, Kalyan Kumar
Balamkundu, Seetharamsing
Wong, Yee Hwa
Nah, Qianhui
Gadi, Vinod
Gnanakalai, Shanmugavel
Chionh, Yok Hian
McBee, Megan E.
Gopal, Pooja
Lim, Siau Hoi
Olivier, Nelson
Buurman, Ed T.
Dick, Thomas
Liu, Chuan Fa
Lescar, Julien
Dedon, Peter C.
Keywords: Science::Biological sciences
Issue Date: 2019
Source: Zhong, W., Pasunooti, K. K., Balamkundu, S., Wong, Y. H., Nah, Q., Gadi, V., Gnanakalai, S., Chionh, Y. H., McBee, M. E., Gopal, P., Lim, S. H., Olivier, N., Buurman, E. T., Dick, T., Liu, C. F., Lescar, J. & Dedon, P. C. (2019). 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), 7788-7805.
Project: ING137070-BIO
MOE2015- T2-2-075
Journal: Journal of Medicinal Chemistry
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.
ISSN: 0022-2623
DOI: 10.1021/acs.jmedchem.9b00582
Rights: © 2019 American Chemical Society. This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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