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

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.