Writer: Kathleen Phillips, (979) 845-2872, ka-phillips@tamu.edu
Contact: Dr. Jim Sacchettini, (979) 862-7636 , sacchett@tamu.edu
COLLEGE STATION - A team of U.S. researchers have begun to demystify the persistence of tuberculosis, according to Dr. Jim Sacchettini, biochemist at Texas A&M University and co-author of a paper appearing Aug. 17 in the journal Nature.
Dr. Jim Sacchettini, biochemist, Texas Agricultural Experiment Station
The research is the first of its kind to point to a way to treat persistent TB. The bacteria that causes the disease, Mycobacterium tuberculosis, can evade the human immune system and drug therapy for perhaps years by living in a persistent and semi-dormant state.
“That’s where our work is unique,” he said. “We began to define the enzymes that are essential for bacterial survival in the persistent stage. We now know what bacteria uses for energy to survive when they become persistent.”
Armed with this information, he said, the team is designing drugs that will kill the persistent bacteria.
Some 3.8 million cases of tuberculosis are diagnosed each year and 2.6 million cases are fatal, according to the World Health Organization. The Texas Department of Health reports that while the state’s cases declined by more than 9 percent in 1999, there are some 1,650 people suffering from the contagious disease in Texas the third largest number of cases in the United States.
Sacchettini explained that TB chemotherapy now being used has two major problems: drug resistance and bacterial persistence.
“Many new strains of TB are resistant to our best drugs,” he said.
One of the reasons for the high resistance is that no new drugs have been developed for TB since the 1970s, so any new strains that have evolved since then have no effective treatment.
Couple that with the fact that the chemotherapy usually prescribed to combat TB takes a minimum of six months of a daily multi-drug dosage. The length of the treatment plan is a disadvantage worldwide in the effort to control this disease, he said.
“A very large group of people on TB drugs become non-compliant,” he said. “They don’t finish drug treatment for some reason, perhaps because they start feeling better or the drugs are not available consistently.”
Health organizations worldwide have tried to stop non-compliance with Directly Observed Treatment plans, known as DOTs, but it is very expensive, especially in under-developed nations, but even in large U.S. cities and rural areas.
“Completion of the drug treatment plan will ultimately lower the risk of becoming drug resistant,” Sacchettini said.
He explained that though something like strep throat can be cured with 14 days of medication, TB has the ability to go into persistent state if a person stops taking medicine too soon.
“TB bacteria live in macrophages, the cells of the immune system, which try to kill the bacteria by making the environment harsh. But TB has figured out a way to live in this environment by changing its metabolism,” Sacchettini said. “It is similar to a human changing his metabolism to adapt to a bitterly cold environment.
“That is sometimes called dormant, latent, or persistent state of TB. The bottom line is TB is able to survive and our best drugs will not work well when it is in this state.”
He said as much as 95 percent of the TB bacteria in an infection are killed in the first couple of weeks of drug treatment. The remaining are what becomes persistent, and extremely difficult to kill with current drugs.
“Even 35 years after drug therapy, dormant TB can re-emerge,” Sacchettini said. “The TB stays at bay in the body waiting for the right moment, such as when the immune system is reduced.”
The problem is that until now, scientists have never truly understood this persistence, he said. His team, led by Drs. Vivek Sharma and Sujata Sharma, did a three-dimensional structure of a TB enzyme essential for persistence using x-ray crystallography in its native form and with an enzyme inhibitor.
They now are using structure based drug design method to make anti-persistence drugs in collaboration with Dr. Ken Duncan at Glaxo Wellcome, a pharmaceutical company with 76 operating companies and more than 50 manufacturing sites worldwide, including two U.S. facilities.
“This means that we now have the potential to develop drugs that kill the persistent TB bacteria,” he said. “We already have great drugs for the acute stage of infection. But with a drug designed to target TB at the persistent stage, we may be able to reduce treatment to only a few weeks which could reduce noncompliance. And that would give us more ability to eradicate TB.”
Sacchettini said that by using robotics to screen millions of TB inhibiting compounds from Glaxco, they could find and make candidate drugs in six months. It would take several more years, however, for the new drug to go through the clinical trials necessary to get approval from the U.S. Food and Drug Administration.
Collaborators with Sacchettini include David G. Russell, Washington University School of Medicine; John D. McKinney, Albert Einstein College of Medicine; and Wai-Tsing Chan, The Rockefeller University.
-30-
