April 25, 2006

COLLEGE STATION - The National Institute of Health has granted $13.7 million for a five-year tuberculosis research project, headed by Dr. Jim Sacchettini and a team of scientists with the Texas Agricultural Experiment Station.

Sacchettini said the team will examine three-dimensional structures of a large number of proteins in the TB genome. Their goal is to discover new drugs to treat the disease.

He said the project is the only large-scale structural biology project in the NIH program that will focus on a single organism.

The team will collaborate on the grant with researchers from the University of California-Los Angeles, University of California-Berkeley and Los Alamos National Laboratories.

"We will work on the proteins (from Mycobacteria TB) which, as drug targets, have the potential of reducing to just a few weeks what is now 6-9 months of chemotherapy," Sacchettini said.

He explained that while TB is curable, most people inflicted with the disease do not finish their treatment because the time required is lengthy.

The bacteria that causes the disease, Mycobacterium TB, can evade the human immune system and drug therapy for years by living in a persistent and dormant state.

"When they awake, the infection can reactivate in the person," he said.

The grant is a continuation of Sacchettini's TB research efforts and is important because every second, someone in the world is newly infected with TB bacilli, according to the United Nation's World Health Organization.

About one-third of the world's population is currently infected with the TB bacillus and about 1.7 million died of TB in 2004, according to the WHO's latest figures.

Sacchettini's research team, which collaborates with 90 laboratories in 15 countries, uses protein crystallography, a method of examining molecules three-dimensionally to find, for example, places that might be good sites for a drug to latch on as it fights the disease. These drug targets can reduce the time required for therapy because the medicine would be a straight shot, so to speak, at the pathogen.

"Most people who start therapy never finish. In some of the most infected countries in the world, it's often difficult to get medicine over the period of several months which is required to cure the disease, he said.

"Our main focus is to look at the structures of targets that, if inactivated by a drug, will kill the bacteria quickly," he explained.

Sacchettini said the team "created a technology pipeline where we can rapidly take any drug target to a 3-D structure in atomic resolution. In many cases a structure can be solved in just a few weeks. Then we can look for potential drugs using ‘grid virtual screening.' That can dramatically improve the drug development process."

Grid virtual screening, he explained, is the use of some 1,000 computers on the Texas A&M University campus to dock drug-like molecules into a protein structure to see if they have potential for drug development.

"We use the computers when they are idle, for example, at night, on weekends and holidays when they are not in use by day workers," he said.

This allows scientists to condense what would have been a couple of years of work into a couple of days, he explained.

"We go from the genetics and microbiology to identify targets, then to the pipeline of researchers in the worldwide consortium to help solve the 3-D structure, then to computerized screening to identify potential drugs," he said.

"Under ideal conditions the whole process can be completed in just a few weeks," he added.

"New drugs are always far away. It takes a long time to come out with a new drug," he said. "Even with these faster methods of research, it still likely will be at least seven years before we have a compound in the testing stage. But without these new technologies, it would have taken at least twice that."