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Fragment-sized EthR inhibitors exhibit exceptionally strong ethionamide boosting effect in whole cell Mycobacterium tuberculosis assays

DOI: 10.1021/acschembio.7b00091 DOI Help

Authors: Petar O. Nikiforov (University of Cambridge) , Michal Blaszczyk (University of Cambridge) , Sachin Surade (University of Cambridge) , Helena I. Boshoff (National Institutes of Health) , Andaleeb Sajid (National Institutes of Health) , Vincent Delorme (Institut Pasteur de Lille) , Nathalie Deboosere (Institut Pasteur de Lille) , Priscille Brodin (Institut Pasteur de Lille) , Alain R. Baulard (Institut Pasteur de Lille) , Clifton E. Barry 3rd (National Institutes of Health; University of Cape Town) , Tom L. Blundell (University of Cambridge) , Chris Abell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: March 2017

Abstract: Small-molecule inhibitors of the mycobacterial transcriptional repressor EthR have previously been shown to act as boosters of the second-line antituberculosis drug ethionamide. Fragment-based drug discovery approaches have been used in the past to make highly potent EthR inhibitors with ethionamide boosting activity both in vitro and ex vivo. Herein, we report the development of fragment-sized EthR ligands with nanomolar minimum effective concentration values for boosting the ethionamide activity in Mycobacterium tuberculosis whole-cell assays.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: European Synchrotron Radiation Facility (ESRF)