Insight

Fall 2008

Innovative TB drug research

The Mycobacteria Research Laboratories is investigating the questions of why tuberculosis often recurs in a person with the infection, and why tuberculosis treatments work so slowly. A recent award from the Bill and Melinda Gates Foundation will help the laboratory to build on new discoveries that question long-held beliefs about recurrence and treatment. The $1.25 million grant, part of the Gates’ initiative to develop faster and more effective tuberculosis treatments, was awarded to Dr. Ian Orme, a Professor in the Department of Microbiology, Immunology and Pathology and member of the Mycobacteria Research Laboratories.

The grant allows Dr. Orme and his research team to pursue the ever-present question facing tuberculosis researchers regarding why it takes nine to 12 months of antibiotics to kill tuberculosis and why, even after such extensive treatment, many patients relapse.

“We think it is because current drugs cannot reach all of the tuberculosis bacterium in an effective manner,” Dr. Orme said. “We know that it kills about 90 percent of the bacteria within the first few weeks of treatment, but the remaining 10 percent persists and is very hard to kill. As yet we know extremely little about these persistent bacteria. But we think we may have now discovered how it might be hiding from the drugs.”

Dr. Orme’s team has new data that shows the persistent bacteria can be found in very discrete areas within lesions in the lung. The bacteria also may exist in a state that tuberculosis experts have previously not considered: the bacteria may be forming microscopic clusters in a biofilm. A biofilm is a thin layer of material that encapsulates the bacteria and protects it from outside elements – in this case, those elements include medications aimed at killing the bacteria.

Tuberculosis researchers around the world have only recently begun to suspect that the tuberculosis bacterium can form a biofilm. Dr. Orme’s research team now has new information suggesting that the biofilm forms about two to three months after infection. According to Dr. Orme, because the drugs cannot get to the bacterium that causes tuberculosis, the persistent bacteria remain in the host and cause relapses after treatment is completed.

The Gates Foundation grant will fund a closer look by Dr. Orme and his team at the area of tissue in the lungs where these bacteria hide, to see if new drugs can kill the persistent bacteria before the biofilm forms or alternatively disrupt the formation of the biofilm to prevent it from protecting the bacteria.

For the past 10 years, the Mycobacteria Research Laboratories has managed the National Institutes of Health’s drug compound testing program for tuberculosis, testing more than 85,000 potential drug compounds since 1997. The laboratory tests new compounds being investigated as potential TB treatments by other universities and by pharmaceutical companies. Compounds being looked at by pharmaceutical companies, other universities and Colorado State researchers are tested in the program. The laboratory has developed numerous tests and models to research tuberculosis drugs today, including specialized tests that facilitate screening large numbers of compounds within shorter time frames.