Scientists Unlock Mystery Behind Proteins that Keep Tuberculosisbacteria Alive; Finding Leads to Research into New Drugtreatments

Tuberculosis researchers have made a surprising discovery that puts a new twist on efforts to develop more effective drugs and vaccines against the infectious disease.

The discovery, made by scientists at Colorado State University’s Mycobacteria Research Laboratory, centers around a group of proteins that scientists have studied for years. However, past research has focused solely on how these proteins, called antigen 85, help defend the body against TB. Antigen 85 activates the immune system after a person is exposed to mycobacterium tuberculosis, the bacteria that causes the disease.

But recently, microbiologists John Belisle, Varalakshmi Vissa and Gurdyal Besra discovered the set of proteins has another face. Antigen 85 also plays a key role in protecting the tuberculosis bacteria from drugs, an unexpected finding that can help develop new treatments that specifically inhibit this function.

"When we confirmed what we had, we were shocked," Belisle said. "This is a major protein that has been studied widely for years in relation to its protective capabilities against TB. It wasn’t until we purified the proteins associated with this enzymatic activity that we realized antigen 85 has two very different roles."

In the study, Belisle and his colleagues confirmed that antigen 85 also functions as an enzyme in forming and maintaining the TB bacteria’s waxy and tough cell wall, which is composed of intricately linked mycolic acids. This tight web makes the cell wall virtually impermeable to many drugs, making the disease difficult to treat.

In addition, the team’s study identified key regions of antigen 85 proteins that are responsible for these important enzymatic activities. Now that it’s known what areas of the proteins carry out their designated function, the researchers now are working with two pharmaceutical companies to create drugs that "turn off" antigen 85’s role in keeping the bacteria alive. Results from the research team’s study was published in the journal, "Science."

Belisle said this discovery already has triggered a shift in developing drugs to fight TB, an infectious disease that spawns 8 million new cases and causes 3 million deaths annually, mostly in developing countries. Antibiotics currently used to treat TB manage to prevent growth of the bacteria, but the long-term drug treatments needed to cure the disease give the organism time to mutate into new, resistant forms. Making treatment even more difficult is the fact that many TB sufferers stop taking antibiotics before the bacteria is eliminated.

"This is a breakthrough because it offers a novel drug target for tuberculosis," Belisle said. "Based on this finding, we can create new drugs that inhibit the enzymatic reactions responsible for keeping the cell wall intact, which will result in the death of the TB bacteria."

Colorado State’s Mycobacteria Research Laboratory, led by Patrick Brennan, is one of a few labs worlwide devoted to studying all aspects of tuberculosis and leprosy. The lab was instrumental in creating a model of the TB bacterium’s cell wall and helped defined which parts are responsible for interacting with normal human cells and causing the disease.

Building on this model, the lab has focused on three main areas: developing new drug treatments against TB, creating vaccines that prevent TB from developing, and improving tests that detect the disease at an earlier stage.