Potential tuberculosis fighter takes an unusual tack

The bacterium Mycobacterium tuberculosis claimed 1.8 million lives worldwide in 2015, according to the World Health Organization, making tuberculosis the deadliest infectious disease on Earth. Scientists led by Deborah T. Hung of Broad Institute report a small molecule, called BRD4592, that inhibits one of the bacterium’s key metabolic enzymes—tryptophan synthase (Nat. Chem. Biol. 2017, DOI: 10.1038/nchembio.2420). BRD4592 shuts down this enzyme, not by binding to its active sites, but by binding in the channel between the enzyme’s subunits. This allosteric binding prevents the enzyme from completing the cycle it uses to make tryptophan. It also blocks indole, an important intermediate en route to tryptophan, from shuttling between the enzyme’s two active sites. Hung’s team believes this is one of the most complicated allosteric inhibitors reported to date. The scientists found that mice metabolized BRD4592 too quickly to evaluate the compound’s efficacy in infected animals, but the team did determine that M. tuberculosis engineered without a tryptophan synthase enzyme were unable to establish an infection in mice. This, Hung’s team believes, makes allosteric inhibition of this enzyme an attractive strategy for fighting tuberculosis.