title: Ligand efficiency driven design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging, and linking approaches.
abstract: 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.
authors.affiliation: Université Lille Nord de France , F-59044 Lille, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Villemagne
authors.forename: Marion
authors.initials: M
authors.lastname: Flipo
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blondiaux
authors.forename: Céline
authors.initials: C
authors.lastname: Crauste
authors.forename: Sandra
authors.initials: S
authors.lastname: Malaquin
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.forename: Catherine
authors.initials: C
authors.lastname: Piveteau
authors.forename: Vincent
authors.initials: V
authors.lastname: Villeret
authors.forename: Priscille
authors.initials: P
authors.lastname: Brodin
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Olivier
authors.initials: O
authors.lastname: Sperandio
authors.forename: Sameh H
authors.initials: SH
authors.lastname: Soror
authors.forename: Alexandre
authors.initials: A
authors.lastname: Wohlkönig
authors.forename: René
authors.initials: R
authors.lastname: Wintjens
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.forename: Alain R
authors.initials: AR
authors.lastname: Baulard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Willand
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D051379:Mice; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000590791:4-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001549:Benzamides; C481661:EthR protein, Mycobacterium tuberculosis; D012097:Repressor Proteins; D013844:Thiazoles