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Selective inhibitors of bacterial t-RNA-(N(1)G37) methyltransferase (TrmD) that demonstrate novel ordering of the lid domain.

Hill PJ, Abibi A, Albert R, Andrews B, Gagnon MM, Gao N, Grebe T, Hajec LI, Huang J, Livchak S, Lahiri SD, McKinney DC, Thresher J, Wang H, Olivier N, Buurman ET
J Med Chem 56 7278-88 (2013)
Related entries: 4mcc, 4mcd

Cited: 24 times
EuropePMC logo PMID: 23981144

Abstract

The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.

Articles - 4mcb mentioned but not cited (2)

  1. Combined Approach of Patch-Surfer and PL-PatchSurfer for Protein-Ligand Binding Prediction in CSAR 2013 and 2014. Zhu X, Shin WH, Kim H, Kihara D. J Chem Inf Model 56 1088-1099 (2016)
  2. Mg2+-Dependent Methyl Transfer by a Knotted Protein: A Molecular Dynamics Simulation and Quantum Mechanics Study. Perlinska AP, Kalek M, Christian T, Hou YM, Sulkowska JI. ACS Catal 10 8058-8068 (2020)


Reviews citing this publication (7)

  1. tRNA modifications regulate translation during cellular stress. Gu C, Begley TJ, Dedon PC. FEBS Lett 588 4287-4296 (2014)
  2. Functions of Bacterial tRNA Modifications: From Ubiquity to Diversity. de Crécy-Lagard V, Jaroch M. Trends Microbiol 29 41-53 (2021)
  3. TrmD: A Methyl Transferase for tRNA Methylation With m1G37. Hou YM, Matsubara R, Takase R, Masuda I, Sulkowska JI. Enzymes 41 89-115 (2017)
  4. Transfer RNA methyltransferases with a SpoU-TrmD  (SPOUT) fold and their modified nucleosides in  tRNA. Hori H. Biomolecules 7 E23 (2017)
  5. tRNA methylation: An unexpected link to bacterial resistance and persistence to antibiotics and beyond. Hou YM, Masuda I, Foster LJ. Wiley Interdiscip Rev RNA 11 e1609 (2020)
  6. Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections. Theuretzbacher U, Blasco B, Duffey M, Piddock LJV. Nat Rev Drug Discov 22 957-975 (2023)
  7. Fragment-Based Lead Discovery Strategies in Antimicrobial Drug Discovery. Konaklieva MI, Plotkin BJ. Antibiotics (Basel) 12 315 (2023)

Articles citing this publication (15)

  1. Structural basis for methyl-donor-dependent and sequence-specific binding to tRNA substrates by knotted methyltransferase TrmD. Ito T, Masuda I, Yoshida K, Goto-Ito S, Sekine S, Suh SW, Hou YM, Yokoyama S. Proc Natl Acad Sci U S A 112 E4197-205 (2015)
  2. A divalent metal ion-dependent N(1)-methyl transfer to G37-tRNA. Sakaguchi R, Lahoud G, Christian T, Gamper H, Hou YM. Chem Biol 21 1351-1360 (2014)
  3. tRNA Methylation Is a Global Determinant of Bacterial Multi-drug Resistance. Masuda I, Matsubara R, Christian T, Rojas ER, Yadavalli SS, Zhang L, Goulian M, Foster LJ, Huang KC, Hou YM. Cell Syst 8 302-314.e8 (2019)
  4. Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches. Whitehouse AJ, Thomas SE, Brown KP, Fanourakis A, Chan DS, Libardo MDJ, Mendes V, Boshoff HIM, Floto RA, Abell C, Blundell TL, Coyne AG. J Med Chem 62 7210-7232 (2019)
  5. Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N1)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism. Zhong W, Pasunooti KK, Balamkundu S, Wong YH, Nah Q, Gadi V, Gnanakalai S, Chionh YH, McBee ME, Gopal P, Lim SH, Olivier N, Buurman ET, Dick T, Liu CF, Lescar J, Dedon PC. J Med Chem 62 7788-7805 (2019)
  6. Structural basis for Sfm1 functioning as a protein arginine methyltransferase. Lv F, Zhang T, Zhou Z, Gao S, Wong CC, Zhou JQ, Ding J. Cell Discov 1 15037 (2015)
  7. Survey and Validation of tRNA Modifications and Their Corresponding Genes in Bacillus subtilis sp Subtilis Strain 168. de Crécy-Lagard V, Ross RL, Jaroch M, Marchand V, Eisenhart C, Brégeon D, Motorin Y, Limbach PA. Biomolecules 10 E977 (2020)
  8. Crystal structure and catalytic mechanism of the essential m1G37 tRNA methyltransferase TrmD from Pseudomonas aeruginosa. Jaroensuk J, Wong YH, Zhong W, Liew CW, Maenpuen S, Sahili AE, Atichartpongkul S, Chionh YH, Nah Q, Thongdee N, McBee ME, Prestwich EG, DeMott MS, Chaiyen P, Mongkolsuk S, Dedon PC, Lescar J, Fuangthong M. RNA 25 1481-1496 (2019)
  9. Evolutionary Adaptation of the Essential tRNA Methyltransferase TrmD to the Signaling Molecule 3',5'-cAMP in Bacteria. Zhang Y, Agrebi R, Bellows LE, Collet JF, Kaever V, Gründling A. J Biol Chem 292 313-327 (2017)
  10. Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification. Thomas SE, Whitehouse AJ, Brown K, Burbaud S, Belardinelli JM, Sangen J, Lahiri R, Libardo MDJ, Gupta P, Malhotra S, Boshoff HIM, Jackson M, Abell C, Coyne AG, Blundell TL, Floto RA, Mendes V. Nucleic Acids Res 48 8099-8112 (2020)
  11. Restriction of S-adenosylmethionine conformational freedom by knotted protein binding sites. Perlinska AP, Stasiulewicz A, Nawrocka EK, Kazimierczuk K, Setny P, Sulkowska JI. PLoS Comput Biol 16 e1007904 (2020)
  12. Chemical biology and medicinal chemistry of RNA methyltransferases. Fischer TR, Meidner L, Schwickert M, Weber M, Zimmermann RA, Kersten C, Schirmeister T, Helm M. Nucleic Acids Res 50 4216-4245 (2022)
  13. Evolutionary repair reveals an unexpected role of the tRNA modification m1G37 in aminoacylation. Clifton BE, Fariz MA, Uechi GI, Laurino P. Nucleic Acids Res 49 12467-12485 (2021)
  14. tRNA methylation resolves codon usage bias at the limit of cell viability. Masuda I, Yamaki Y, Detroja R, Tagore S, Moore H, Maharjan S, Nakano Y, Christian T, Matsubara R, Lowe TM, Frenkel-Morgenstern M, Hou YM. Cell Rep 41 111539 (2022)
  15. Synthesis, Characterization, and Biological Evaluation of Novel 7-Oxo-7H-thiazolo[3,2-b]-1,2,4-triazine-2-carboxylic Acid Derivatives. Cai D, Li T, Xie Q, Yu X, Xu W, Chen Y, Jin Z, Hu C. Molecules 25 E1307 (2020)


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