 |
PDBsum entry 3g1m
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
3g1m
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Synthetic ethr inhibitors boost antituberculous activity of ethionamide.
|
|
|
Authors
|
|
N.Willand,
B.Dirié,
X.Carette,
P.Bifani,
A.Singhal,
M.Desroses,
F.Leroux,
E.Willery,
V.Mathys,
R.Déprez-Poulain,
G.Delcroix,
F.Frénois,
M.Aumercier,
C.Locht,
V.Villeret,
B.Déprez,
A.R.Baulard.
|
|
|
Ref.
|
|
Nat Med, 2009,
15,
537-544.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The side effects associated with tuberculosis therapy bring with them the risk
of noncompliance and subsequent drug resistance. Increasing the therapeutic
index of antituberculosis drugs should thus improve treatment effectiveness.
Several antituberculosis compounds require in situ metabolic activation to
become inhibitory. Various thiocarbamide-containing drugs, including
ethionamide, are activated by the mycobacterial monooxygenase EthA, the
production of which is controlled by the transcriptional repressor EthR. Here we
identify drug-like inhibitors of EthR that boost the bioactivation of
ethionamide. Compounds designed and screened for their capacity to inhibit
EthR-DNA interaction were co-crystallized with EthR. We exploited the
three-dimensional structures of the complexes for the synthesis of improved
analogs that boosted the ethionamide potency in culture more than tenfold. In
Mycobacterium tuberculosis-infected mice, one of these analogs, BDM31343,
enabled a substantially reduced dose of ethionamide to lessen the mycobacterial
load as efficiently as the conventional higher-dose treatment. This provides
proof of concept that inhibiting EthR improves the therapeutic index of
thiocarbamide derivatives, which should prompt reconsideration of their use as
first-line drugs.
|
|
|
|
|
|
|
|
Figure 4.
The formation of the hydrogen bond between Asn179 and the
oxygen atom of the carbonyl function of BDM31381 is illustrated
by the dotted pink line.
|
|
Figure 5.
All of the structures obtained belong to space group
P4[1]2[1]2, which allows for objective comparison and
measurements.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Med
(2009,
15,
537-544)
copyright 2009.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Insights into mechanisms of induction and ligands recognition in the transcriptional repressor ethr from mycobacterium tuberculosis.
|
|
|
Authors
|
|
F.Frénois,
A.R.Baulard,
V.Villeret.
|
|
|
Ref.
|
|
Tuberculosis (edinb), 2006,
86,
110-114.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #2
|
|
|
Title
|
|
Structure of ethr in a ligand bound conformation reveals therapeutic perspectives against tuberculosis.
|
|
|
Authors
|
|
F.Frénois,
J.Engohang-Ndong,
C.Locht,
A.R.Baulard,
V.Villeret.
|
|
|
Ref.
|
|
Mol Cell, 2004,
16,
301-307.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 3.
Figure 3. Stereoviews of Ligand Binding Regions(A) Ligand
recognition by EthR. Only residues for which atoms lie in a 5
Å sphere around the ligand are depicted. The ligand is
shown in dark green, while carbons, nitrogens, oxygens, and
sulfur that belong to the amino acids are in gold, light blue,
red, and green, respectively. There is a buried water molecule
hydrogen bonded to N179. Recognition of the ligand involves
residues from the six helices forming the ligand binding
domain.(B) Comparison of ligand binding regions of EthR and
QacR with their respective ligands. Superimposition of the core
ligand binding region (α4–α9) of EthR (in blue) in complex
with HexOc (in dark green) and that of QacR (in brown) in
complex with ethidium (in gold) or rhodamine (dark red). F114
may play an important role in EthR induction, in a way analogous
to that played by the Y92 region switch in QacR. The QacR
structure highlights the multisite binding pocket found in this
repressor. Although both repressors share the ligand entrance
and have adjacent partially overlapping binding sites, they have
nevertheless drastically divergent overall binding cavities. The
ligand in EthR is mainly deeply buried in the hydrophobic core
of the ligand binding domain, in a cavity that develops parallel
to the axes of helices α4 and α7. In contrast, the multisite
binding pocket in QacR runs nearly parallel to α6. The
displacement of α5 in EthR relative to that of QacR abolishes
this cavity in EthR.
|
|
Figure 4.
Figure 4. Synergistic Effect of Benzylacetone and ETH on
the Growth of M. smegmatisThe synergistic effect (see
Experimental Procedures) was assayed by spotting 4 μl of serial
dilutions (A: 10^−2; B: 10^−3; C: 10^−4; D: 10^−5) of a
mid-log phase culture of M. smegmatis mc^2155 onto LB plates
containing no drug, 5 μg/ml ETH alone (ETH), 1 mM benzylacetone
alone (BA), or a combination of both compounds (ETH + BA).
Plates were incubated 4 days at 37°C. Reduction of growth
was observed only on ETH + BA (compare spots A on each plate).
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from Cell Press
|
|
|
Secondary reference #3
|
|
|
Title
|
|
Ethr, A repressor of the tetr/camr family implicated in ethionamide resistance in mycobacteria, Octamerizes cooperatively on its operator.
|
|
|
Authors
|
|
J.Engohang-Ndong,
D.Baillat,
M.Aumercier,
F.Bellefontaine,
G.S.Besra,
C.Locht,
A.R.Baulard.
|
|
|
Ref.
|
|
Mol Microbiol, 2004,
51,
175-188.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
