Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays.
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.
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
Petar O
PO
Nikiforov
Department of Biochemistry, University of Cambridge , 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
Michal
M
Blaszczyk
Department of Biochemistry, University of Cambridge , 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
Sachin
S
Surade
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
Helena I
HI
Boshoff
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
Andaleeb
A
Sajid
CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, Université de Lille , F-59000 Lille, France.
Vincent
V
Delorme
CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, Université de Lille , F-59000 Lille, France.
Nathalie
N
Deboosere
CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, Université de Lille , F-59000 Lille, France.
Priscille
P
Brodin
CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, Université de Lille , F-59000 Lille, France.
Alain R
AR
Baulard
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.|Institute for Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town 7935, South Africa.
Clifton E
CE
Barry
Department of Biochemistry, University of Cambridge , 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
Tom L
TL
Blundell
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
Chris
0000-0001-9174-1987
C
Abell
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D055808:Drug Discovery; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005000:Ethionamide / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C481661:EthR protein, Mycobacterium tuberculosis; D008024:Ligands; D012097:Repressor Proteins; D005000:Ethionamide