Recent study discovers new potential approach to combating TB

A study recently published in the ACS Chemical Biology journal potentially discovered a new approach to combating tuberculosis at a critical time when antibiotic resistant Mycobacterium tuberculosis cases are on the rise.

The new methodology sought to create an alternative to antibiotic TB treatment. Researchers instead targeted CLpP, a key enzyme to cellular function of TB bacteria, in an attempt to prevent it from functioning.

"ClpP has emerged over the last decade or so as a potential drug target in bacteria because they require it to either live or to cause disease," Jason Sello, senior author and associate professor of chemistry at Brown, said. "Our findings indicate that chemical inhibition of the essential ClpP enzyme in Mycobacterium tuberculosis is a viable strategy in anti-tuberculosis drug development."

The research team became the first to study what would happen if the ClpP enzyme was blocked; they hoped this would be key in developing an alternative route to combating TB.

"If you can inhibit the function of the enzyme with a small molecule, then you can kill the bacterium," Sello said. "When we began our work, the validity of this approach hadn't been demonstrated."

Using an in vitro test tube assay, developed by Robert Sauer of MIT and postdoctoral fellow Karl Schmitz, researchers were able to observe the hypothesis play out as estimated; the enzyme was successfully inhibited. This opened the door to new anti-TB drug developments.

"Our data validate ClpP as a viable, antibacterial drug target," Sello said. "We have a high degree of confidence that inactivating ClpP will inhibit the growth of Mycobacterium tuberculosis. In principle, a pharmaceutical company could develop new tuberculosis drugs by using the structure of β-lactone 7 as a starting point or by using ClpP inhibition as a design strategy."