Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches

Baptiste Villemagne (1) , Marion Flipo (2) , Nicolas Blondiaux , Celine Crauste (3) , Sandra Malaquin (1) , Florence Leroux (4) , Catherine Piveteau (2) , Vincent Villeret (5) , Priscille Brodin (6) , Bruno O. Villoutreix (7) , Olivier Sperandio , Sameh H. Soror , Alexandre Wohlkönig , René Wintjens , Benoit Deprez , Alain R. Baulard , Nicolas Willand

1 Biostructures et Decouverte de Medicament
2 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
3 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
4 CDithem Platform
5 UGSF - Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576
6 Institut Pasteur Korea - Institut Pasteur de Corée
7 MTI - Molécules Thérapeutiques in silico

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, ligand efficiency driven design for the rapid discovery and optimization of new chemotypes of EthR ligands starting from a fragment. The design, synthesis, in vitro and ex vivo activities of these compounds will be discussed.

Domaines: Sciences du Vivant [q-bio]

Baptiste Villemagne, Marion Flipo, Nicolas Blondiaux, Celine Crauste, Sandra Malaquin, et al.. Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches. Journal of Medicinal Chemistry, 2014, 57 (11), pp.4876-4888. ⟨10.1021/jm500422b⟩. ⟨hal-02309782⟩