Targeting of Fumarate Hydratase from <i>Mycobacterium tuberculosis</i> Using Allosteric Inhibitors with a Dimeric-Binding Mode.
Whitehouse AJ, Libardo MDJ, Kasbekar M, Brear PD, Fischer G, Thomas CJ, Barry CE, Boshoff HIM, Coyne AG, Abell C.
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 <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of <i>Mtb</i> 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 <i>Mtb</i> in vitro identified compounds with potent minimum inhibitory concentrations.