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PDBsum entry 5nim
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DNA binding protein
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PDB id
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5nim
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References listed in PDB file
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Key reference
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Title
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New active leads for tuberculosis booster drugs by structure-Based drug discovery.
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Authors
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N.J.Tatum,
J.W.Liebeschuetz,
J.C.Cole,
R.Frita,
A.Herledan,
A.R.Baulard,
N.Willand,
E.Pohl.
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Ref.
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Org Biomol Chem, 2017,
15,
10245-10255.
[DOI no: ]
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PubMed id
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Abstract
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The transcriptional repressor EthR from Mycobacterium tuberculosis, a member of
the TetR family of prokaryotic homo-dimeric transcription factors, controls the
expression of the mycobacterial mono-oxygenase EthA. EthA is responsible for the
bio-activation of the second-line tuberculosis pro-drug ethionamide, and
consequently EthR inhibitors boost drug efficacy. Here, we present a
comprehensive in silico structure-based screening protocol that led to the
identification of a number of novel scaffolds of EthR inhibitors in subsequent
biophysical screening by thermal shift assay. Growth inhibition assays
demonstrated that five of the twenty biophysical hits were capable of boosting
ethionamide activity in vitro, with the best novel scaffold displaying an
EC50of 34 μM. In addition, the co-crystal structures of EthR with
four new ligands at resolution ranging from 2.1 to 1.4 Å confirm the binding
and inactivation mode, and will enable future lead development.
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