Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37- N1)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism

Wenhe Zhong, Kalyan Kumar Pasunooti, Seetharamsing Balamkundu, Yee Hwa Wong, Qianhui Nah, Vinod Gadi, Shanmugavel Gnanakalai, Yok Hian Chionh, Megan E. McBee, Pooja Gopal, Siau Hoi Lim, Nelson Olivier, Ed T. Buurman, Thomas Dick, Chuan Fa Liu, Julien Lescar, Peter C. Dedon

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7788-7805
Number of pages18
JournalJournal of medicinal chemistry
Volume62
Issue number17
DOIs
StatePublished - Sep 12 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    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. https://doi.org/10.1021/acs.jmedchem.9b00582