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J Med Chem. 2019 Dec 12;62(23):10586-10604. doi: 10.1021/acs.jmedchem.9b01203. Epub 2019 Sep 27.

Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode.

Author information

1
Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , U.K.
2
Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology , National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda , Maryland 20892 , United States.
3
National Center for Advancing Translational Sciences , National Institutes of Health , Bethesda , Maryland 20850 , United States.
4
Department of Biochemistry , University of Cambridge , Tennis Court Road , Cambridge , CB2 1GA , U.K.

Abstract

With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations.

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