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
"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 www.niaid.nih.gov.