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PDBsum entry 6qo2
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References listed in PDB file
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Key reference
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Title
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Fragment-Based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.
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Authors
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S.E.Thomas,
A.J.Whitehouse,
K.Brown,
S.Burbaud,
J.M.Belardinelli,
J.Sangen,
R.Lahiri,
M.D.J.Libardo,
P.Gupta,
S.Malhotra,
H.I.M.Boshoff,
M.Jackson,
C.Abell,
A.G.Coyne,
T.L.Blundell,
R.A.Floto,
V.Mendes.
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Ref.
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Nucleic Acids Res, 2020,
48,
8099-8112.
[DOI no: ]
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PubMed id
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Abstract
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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.
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