Rutgers research team discovers new class of anti-tuberculosis drugs

A research team at Rutgers University recently determined the three-dimensional structure of the target of the anti-tuberculosis drug rifampin and discovered a new class of drugs that could potentially kill multi-drug resistant tuberculosis (TB) bacteria.

Rifampin has been used as an anti-TB therapy since it was first manufactured in 1961. In the years since, however, a rifampin-resistant TB bacteria has developed, posing a significant public health risk.

Rifampin-resistant TB bacteria develops when TB bacteria acquire mutations that alter the binding site for rifampin on the enzyme it inhibits in the disease, called Mtb RNA polymerase (Mtb RNAP). The alternations of the binding site prevent the treatment from binding and inhibiting Mtb RNAP, which prevents the killing of TB bacteria.

In a paper released by Rutgers researcher Richard H. Ebright and his team, the scientists explain that the three-dimensional structures Mtb RNAP were determined by use of x-ray crystallography and are at a resolution sufficient to define the positions, conformations and interactions of individual amino acid residues of Mtb RNAP.

“The results reveal the interactions between Mtb RNAP and rifampin, reveal the mechanism by which rifampin inhibits Mtb RNAP, and enable rational, structure-based design of improved rifampin derivatives for inhibition of Mtb RNAP,” the team said.

The Rutgers team also revealed the discovery of new, non-rifampin related compounds called N(alpha)-aroyl-N-aryl-phenylalaninamides (AAPs), which selectively inhibit Mtb RNAP, potently and selectively killing TB bacteria.

Ebright said the structure of Mtb RNAP had been the “Holy Grail” for TB drug discovery targeting Mtb RNAP, and that AAPs represented an entirely new class of Mtb RNAP inhibitors. He added that AAPs were, without question, the most promising Mtb RNAP inhibitors for anti-TB drug development since the creation of rifampin.

Support for the study was provided by the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, and contracts from the Global Alliance for TB Drug Development.