Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.
Anti-Bacterial Agents
/ chemistry
Bacterial Proteins
/ antagonists & inhibitors
Binding Sites
Drug Discovery
/ methods
Enzyme Inhibitors
/ chemistry
Molecular Docking Simulation
Mycobacterium abscessus
/ drug effects
Mycobacterium leprae
/ drug effects
Protein Binding
RNA, Transfer
/ metabolism
tRNA Methyltransferases
/ antagonists & inhibitors
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
20 08 2020
20 08 2020
Historique:
accepted:
15
06
2020
revised:
10
06
2020
received:
13
03
2020
pubmed:
1
7
2020
medline:
11
11
2020
entrez:
1
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32602532
pii: 5865065
doi: 10.1093/nar/gkaa539
pmc: PMC7641325
doi:
Substances chimiques
Anti-Bacterial Agents
0
Bacterial Proteins
0
Enzyme Inhibitors
0
RNA, Transfer
9014-25-9
tRNA Methyltransferases
EC 2.1.1.-
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8099-8112Subventions
Organisme : Wellcome Trust
ID : 200814 Z 16 Z
Pays : United Kingdom
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Lancet Respir Med. 2018 Apr;6(4):299-314
pubmed: 29595511
J Mol Biol. 2017 Aug 18;429(17):2677-2693
pubmed: 28648615
PLoS One. 2013 Dec 30;8(12):e84065
pubmed: 24386332
ACS Infect Dis. 2019 Mar 8;5(3):326-335
pubmed: 30682246
PLoS One. 2010 May 24;5(5):e10777
pubmed: 20520722
Nat Rev Drug Discov. 2016 Sep;15(9):605-619
pubmed: 27417849
J Infect Dis. 2010 Jun 1;201(11):1736-42
pubmed: 20402595
Nat Struct Mol Biol. 2016 Oct;23(10):941-948
pubmed: 27571175
J Clin Microbiol. 1988 Jan;26(1):18-21
pubmed: 3125213
Nat Rev Microbiol. 2010 Jun;8(6):423-35
pubmed: 20440275
Mol Microbiol. 2003 Apr;48(1):77-84
pubmed: 12657046
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Cell Syst. 2019 Apr 24;8(4):302-314.e8
pubmed: 30981730
ChemMedChem. 2014 Dec;9(12):2708-17
pubmed: 25164952
Int J Lepr Other Mycobact Dis. 1968 Jan-Mar;36(1):78-82
pubmed: 4869698
Curr Opin Infect Dis. 2017 Aug;30(4):404-409
pubmed: 28548990
Int J Lepr Other Mycobact Dis. 2001 Mar;69(1):1-12
pubmed: 11480310
Science. 1989 May 26;244(4907):986-9
pubmed: 2471265
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):355-67
pubmed: 21460454
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):282-92
pubmed: 21460446
Sci Rep. 2018 Mar 22;8(1):5016
pubmed: 29567948
Drug Discov Today. 2017 Mar;22(3):546-554
pubmed: 27742535
Drug Discov Today. 2018 Aug;23(8):1502-1519
pubmed: 29635026
Nucleic Acids Res. 1997 Mar 1;25(5):955-64
pubmed: 9023104
Thorax. 2016 Jan;71 Suppl 1:i1-22
pubmed: 26666259
Biomolecules. 2017 Mar 21;7(1):
pubmed: 28335556
Nat Struct Mol Biol. 2009 Oct;16(10):1109-15
pubmed: 19749755
J Med Chem. 2019 Aug 8;62(15):7210-7232
pubmed: 31282680
Nat Commun. 2015 Feb 25;6:6267
pubmed: 25711368
Tuberculosis (Edinb). 2015 Mar;95(2):142-8
pubmed: 25613812
Philos Trans A Math Phys Eng Sci. 2019 Jun 17;377(2147):20180422
pubmed: 31030650
Methods Mol Biol. 2015;1285:177-99
pubmed: 25779316
Sci Rep. 2017 Apr 20;7(1):969
pubmed: 28428565
EMBO J. 2001 Jan 15;20(1-2):231-9
pubmed: 11226173
EMBO J. 2001 Sep 3;20(17):4863-73
pubmed: 11532950
PLoS Pathog. 2011 Sep;7(9):e1002251
pubmed: 21980284
J Med Chem. 2013 Sep 26;56(18):7278-88
pubmed: 23981144
Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4197-205
pubmed: 26183229
ACS Med Chem Lett. 2014 May 09;5(6):616-8
pubmed: 24944729
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
J Med Chem. 2016 May 12;59(9):4314-25
pubmed: 27043011
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
EMBO J. 2003 Jun 2;22(11):2593-603
pubmed: 12773376
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
J Cyst Fibros. 2015 Jan;14(1):53-62
pubmed: 24917112
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):293-302
pubmed: 21460447
mBio. 2017 Jan 17;8(1):
pubmed: 28096490
Acta Crystallogr D Biol Crystallogr. 2013 Jul;69(Pt 7):1204-14
pubmed: 23793146
Antimicrob Agents Chemother. 2016 Apr 22;60(5):3132-7
pubmed: 26883701
J Med Microbiol. 2005 Mar;54(Pt 3):235-242
pubmed: 15713606
J Mol Microbiol Biotechnol. 2002 Jan;4(1):71-5
pubmed: 11763972
Drug Discov Today. 2005 Dec;10(23-24):1675-82
pubmed: 16376828
Nucleic Acids Res. 2016 Jul 8;44(W1):W54-7
pubmed: 27174935
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
Nat Methods. 2007 Feb;4(2):147-52
pubmed: 17179933