Colorado State Receives $6.25 Million from National Institutes of Health to Discover and Test New Drugs Against Tuberculosis

Two groups of investigators in Colorado State University’s microbiology department have received $6.25 million to continue groundbreaking research programs into drugs that can cure tuberculosis.

A research team led by Patrick Brennan, professor of microbiology, will receive more than $2.9 million for four years to identify drugs that can cure the disease. A University Distinguished Professor, Brennan and teammates will work in cooperation with a major pharmaceutical firm to do so.

Another group of researchers led by Ian Orme, professor of microbiology, has received a seven-year, $3.4 million contract to test the efficacy of proposed anti-tuberculosis drugs. Funding comes from the National Institutes of Health.

Brennan’s approach involves an unusual collaboration with pharmaceutical manufacturer SmithKline Beecham. His drug discovery program will fund two postdoctoral students to work on site at SmithKline Beecham headquarters near Philadelphia, using the company’s extensive testing and research infrastructure to find matches for potential anti-TB compounds identified at Colorado State.

American research on vaccines and anti-TB drugs almost ceased a few decades ago as public health officials assumed the disease was on the way to eradication, just as smallpox was. However, tuberculosis is now the leading bacterial killer in the world, causing 10 million new cases and 3 million deaths each year. It is resurgent in developing countries and, in America, in prison populations, among the homeless and in HIV/AIDS-infected patients, Orme said. A factor in its comeback and one of particular concern is that some strains are resistant to several anti-TB drugs. Easily spread through modern airline travel worldwide, Orme describes them as "a global disaster."

Brennan and colleagues are looking at older drugs, natural products and synthesized compounds that show some anti-TB mechanism. Those that do are sent to the postdoctoral researchers at SmithKline Beecham, who will use the company’s automated "high-throughput" system. This testing procedure can scan up to eight million compounds, matching existing drugs with those possessing anti-TB qualities.

"The basic assays from our labs go to SmithKline Beecham, and personnel then screen all the compounds in their banks against our assays and their own," Brennan said. "Once we have a match we come back to Ian, who tests it in his lab, looking for efficacy and then making sure there’s no toxicity associated with it."

Orme’s team will screen the most promising drugs in vitro and in modeling systems, examining pharmacokinetics, safety and other matters.

"There really isn’t much to testing that we don’t have a hand in," he said. "Our lab’s been doing it all, initially funneling a large number of drugs (through testing) and winnowing them down."

Orme’s contract calls for testing approximately 10 promising anti-tubercular drugs each year, although he anticipates investigating perhaps twice that number.

Brennan said progress toward finding effective drugs is hampered by economics, since recouping research and development costs will be difficult.

"There isn’t much money in tuberculosis drugs," he said. "It’s a poor person’s disease, found primarily in developing countries." SmithKline Beecham’s cooperation reflects their long tradition of antibacterial study, he said.

In a different approach to the tuberculosis threat, Orme heads a 10-person team that develops possible TB vaccines. In addition, since 1992, with a grant from the National Institutes of Health, they have operated a TB vaccine screening program that has examined dozens of experimental vaccines. Orme thinks both drugs and vaccines will be necessary to deal with tuberculosis.

"In the long run we’re going to have to deal with tuberculosis by vaccination," Orme said. "In the short term, we’re going to have to use drugs."

Brennan heads Colorado State’s Mycobacteria Research Laboratory, a group of researchers within the microbiology department that investigates tuberculosis. Research lab work related to the drug discovery program includes a study of how simple sugars are synthesized in TB cell walls, conducted by professor Michael McNeil, and the application of compounds based on effective fungicides and herbicides in the battle against TB, carried out by assistant professor Dean Crick.