6 research outputs found
Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches
No full textTuberculosis
remains a major cause of mortality and morbidity,
killing each year more than one million people. Although the combined
use of first line antibiotics (isoniazid, rifampicin, pyrazinamide,
and ethambutol) is efficient to treat most patients, the rapid emergence
of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional
repressor EthR is a key player in the control of second-line drugs
bioactivation such as ethionamide and has been shown to impair the
sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. As a way to identify new potent ligands of this
protein, we have developed fragment-based approaches. In the current
study, we combined surface plasmon resonance assay, X-ray crystallography,
and ligand efficiency driven design for the rapid discovery and optimization
of new chemotypes of EthR ligands starting from a fragment. The design,
synthesis, and in vitro and ex vivo activities of these compounds
will be discussed
Discovery of Novel <i>N</i>-Phenylphenoxyacetamide Derivatives as EthR Inhibitors and Ethionamide Boosters by Combining High-Throughput Screening and Synthesis
No full textIn this paper, we describe the screening of a 14640-compound
library
using a novel whole mycobacteria phenotypic assay to discover inhibitors
of EthR, a transcriptional repressor implicated in the innate resistance
of Mycobacterium tuberculosis to the
second-line antituberculosis drug ethionamide. From this screening
a new chemical family of EthR inhibitors bearing an <i>N</i>-phenylphenoxyacetamide motif was identified. The X-ray structure
of the most potent compound crystallized with EthR inspired the synthesis
of a 960-member focused library. These compounds were tested in vitro
using a rapid thermal shift assay on EthR to accelerate the optimization.
The best compounds were synthesized on a larger scale and confirmed
as potent ethionamide boosters on M. tuberculosis-infected macrophages. Finally, the cocrystallization of the best
optimized analogue with EthR revealed an unexpected reorientation
of the ligand in the binding pocket
Ethionamide Boosters. 2. Combining Bioisosteric Replacement and Structure-Based Drug Design To Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors
No full textMycobacterial transcriptional repressor EthR controls
the expression
of EthA, the bacterial monooxygenase activating ethionamide, and is
thus largely responsible for the low sensitivity of the human pathogen <i>Mycobacterium tuberculosis</i> to this antibiotic. We recently
reported structure–activity relationships of a series of 1,2,4-oxadiazole
EthR inhibitors leading to the discovery of potent ethionamide boosters.
Despite high metabolic stability, pharmacokinetic evaluation revealed
poor mice exposure; therefore, a second phase of optimization was
required. Herein a structure–property relationship study is
reported according to the replacement of the two aromatic heterocycles:
2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using
a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR
and on the human pathogen <i>Mycobacterium tuberculosis</i>. Thanks to this process, we identified compound <b>42</b> (BDM41906), which displays improved efficacy in addition to high
exposure to mice after oral administration
