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

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• 作者：Baptiste Villemagne ; Marion Flipo ; Nicolas Blondiaux ; C茅line Crauste ; Sandra Malaquin ; Florence Leroux ; Catherine Piveteau ; Vincent Villeret ; Priscille Brodin ; Bruno O. Villoutreix ; Olivier Sperandio ; Sameh H. Soror ; Alexandre Wohlk枚nig ; Ren茅 Wintjens ; Benoit Deprez ; Alain R. Baulard ; Nicolas Willand
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4876-4888
• 全文大小：735K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

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.