title: A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.
abstract: With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. ca26@cam.ac.uk.
authors.forename: Petar O
authors.initials: PO
authors.lastname: Nikiforov
authors.forename: Sachin
authors.initials: S
authors.lastname: Surade
authors.forename: Michal
authors.initials: M
authors.lastname: Blaszczyk
authors.forename: Vincent
authors.initials: V
authors.lastname: Delorme
authors.forename: Priscille
authors.initials: P
authors.lastname: Brodin
authors.forename: Alain R
authors.initials: AR
authors.lastname: Baulard
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
mesh_terms: D018360:Crystallography, X-Ray; D005000:Ethionamide / Q000737:chemistry* / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012097:Repressor Proteins / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C481661:EthR protein, Mycobacterium tuberculosis; D012097:Repressor Proteins; D054852:Small Molecule Libraries; D005000:Ethionamide