4M3F: Rapid And Efficient Design Of New Inhibitors Of Mycobacterium Tuberculosis Transcriptional Repressor Ethr Using Fragment Growing, Merging And Linking Approaches

Tuberculosis 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.
PDB ID: 4M3FDownload
MMDB ID: 120983
PDB Deposition Date: 2013/8/6
Updated in MMDB: 2014/06
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 4M3F: dimeric; determined by author and by software (PISA)
Molecular Components in 4M3F
Label Count Molecule
Proteins (2 molecules)
Hth-type Transcriptional Regulator Ethr
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

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