Tuberculosis (TB), the world's leading killer among infectious diseases, has not faced an effective new class of drugs for more than 30 years. Now, a promising new weapon in the fight against that disease -- which kills one person every 15 seconds across the globe -- has been reported in the current issue of Nature. The candidate drug, developed by scientists at PathoGenesis Corporation in Seattle, has unique properties that may make it superior to current anti-TB compounds. Collaborative studies performed with scientists at the National Institute of Allergy and Infectious Diseases (NIAID) determined how the drug works.
Because TB hits hardest in impoverished regions where people cannot afford drug treatment, pharmaceutical companies have been reluctant to invest in research on new drugs. "Infectious diseases like TB, AIDS and malaria exact a devastating toll worldwide, particularly in developing countries," states Anthony S. Fauci, M.D., director of NIAID. "Public-private collaborations like this can effectively accelerate research on new ways to treat and prevent these diseases."
The incidence of TB, a chronic bacterial infection caused by Mycobacterium tuberculosis (MTB), has been increasing for several years, in part because HIV infection increases susceptibility to MTB. In addition, multi-drug resistant (MDR) strains of the bacteria are spreading throughout the globe, making new TB drugs necessary. Even MTB strains that are susceptible to current drugs are often difficult to eliminate because they can enter a latent state similar to hibernation where they hide away in low-oxygen regions of the lungs.
To facilitate TB drug development, NIAID and PathoGenesis established a research collaboration focused on developing a new class of anti-TB agents that attack the protective cell wall of MTB. "The company's expertise in chemistry and molecular biology meshed well with our expertise in cell wall biochemistry," says Clifton E. Barry III, Ph.D., chief of the tuberculosis research section in NIAID's Laboratory of Host Defenses. "Our collaboration demonstrates the value of combining complementary efforts to find creative solutions to global disease."
The idea for the newest drug candidate arose when the scientists scoured the literature for unrecognized compounds with anti-TB activity. They noted that a compound -- originally investigated by another company for use in the treatment of cancer -- also was reported to have activity against MTB. This compound had not been pursued, however, because it tended to cause mutations. PathoGenesis chemists made 328 chemical variants of the original compound, which the team then tested for anti-TB activity in the test tube and in mice. Many of the new compounds destroyed MTB as well as or better than the original drug but lacked its undesirable mutation-causing properties. In laboratory assays, these variants also killed all MDR strains of MTB tested. One of these compounds, called PA-824, was selected for further study because it showed promising activity in animal models of TB.
"At the time, we were collaborating with Dr. Barry's laboratory on another project involving bacterial cell walls," says Dr. Kendall Stover, senior director of research biology at PathoGenesis. "Therefore, we redirected some of our efforts to figure out how PA-824 worked. Dr. Barry's laboratory assisted us in investigating PA-824's novel mechanism for killing M. tuberculosis. We discovered that the new drug acts in part by preventing MTB from forming an important fatty acid component of its cell walls. We were quite fortunate to collaborate with Dr. Barry's lab, because NIAID's cell wall biochemistry expertise nicely complemented ours."
The researchers discovered another advantage of PA-824 over existing agents. Most anti-TB drugs must first be activated by MTB itself, and MDR strains can resist these agents by blocking their entrance into the bacteria or preventing their activation. PA-824, however, may use a 'Trojan horse' approach to bypass the MTB sentries, allowing the drug to target the cell wall and kill the bacteria. "We continue to study this property as an important element of other new anti-TB compounds," says Dr. Barry.
The partnership with PathoGenesis was arranged through a Cooperative Research and Development Agreement (CRADA) from NIAID. CRADAs do not award money to drug companies but rather are research agreements through which public and private organizations share resources. CRADAs therefore provide one way for companies to pursue promising but "low-profit" drugs -- such as those for TB, AIDS and malaria -- without spending huge amounts of money starting up new laboratories.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose, and treat illness such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Reference:
Stover, CK et al. A nitroimidazopyran drug candidate for the treatment of active and latent tuberculosis. Nature 2000;405:926-66.
Journal
Nature