6qr8 › Citations

Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.

Figure 1.
Figure 2.
Figure 3.
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
OpenAccess logo Nucleic Acids Res 48 8099-8112 (2020)

Cited: 12 times
EuropePMC logo PMID: 32602532

Abstract

Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs.

Reviews - 6qr8 mentioned but not cited (1)

  1. Potential therapeutic targets from Mycobacterium abscessus (Mab): recently reported efforts towards the discovery of novel antibacterial agents to treat Mab infections. Addison W, Frederickson M, Coyne AG, Abell C. RSC Med Chem 13 392-404 (2022)

Articles - 6qr8 mentioned but not cited (2)

  1. 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)
  2. 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)


Reviews citing this publication (5)

  1. Fragment-to-Lead Medicinal Chemistry Publications in 2020. de Esch IJP, Erlanson DA, Jahnke W, Johnson CN, Walsh L. J Med Chem 65 84-99 (2022)
  2. Pipeline of anti-Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities. Egorova A, Jackson M, Gavrilyuk V, Makarov V. Med Res Rev 41 2350-2387 (2021)
  3. Management of Mycobacterium avium complex and Mycobacterium abscessus pulmonary disease: therapeutic advances and emerging treatments. Kumar K, Daley CL, Griffith DE, Loebinger MR. Eur Respir Rev 31 210212 (2022)
  4. Fragment-Based Drug Discovery against Mycobacteria: The Success and Challenges. Togre NS, Vargas AM, Bhargavi G, Mallakuntla MK, Tiwari S. Int J Mol Sci 23 10669 (2022)
  5. Fragment-Based Lead Discovery Strategies in Antimicrobial Drug Discovery. Konaklieva MI, Plotkin BJ. Antibiotics (Basel) 12 315 (2023)

Articles citing this publication (4)

  1. A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis. Gupta P, Thomas SE, Zaidan SA, Pasillas MA, Cory-Wright J, Sebastián-Pérez V, Burgess A, Cattermole E, Meghir C, Abell C, Coyne AG, Jacobs WR, Blundell TL, Tiwari S, Mendes V. Comput Struct Biotechnol J 19 3491-3506 (2021)
  2. 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)
  3. 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)
  4. 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)


Quick links