Experimental TB Drug Explodes Bacteria
from the Inside Out
Research Advance May Lead to New Ways to Attack Latent TB and
An international team of biochemists has discovered how an experimental
drug unleashes its destructive force inside the bacteria that cause
tuberculosis (TB). The finding could help scientists develop ways
to treat dormant TB infections, and suggests a strategy for drug
development against other bacteria as well.
A report describing the research, led by Clifton E. Barry, III,
Ph.D., of the National Institute of Allergy and Infectious Diseases
(NIAID), part of the National Institutes of Health, is published
in the Nov. 28 issue of Science. Dr. Barry's collaborators included
scientists from NIAID and from the Novartis Institute for Tropical
Diseases in Singapore.
One-third of the world's population is infected with Mycobacterium
tuberculosis (M. tb), the bacteria that cause TB. "Currently, there
are no drugs available that specifically target latent tuberculosis
infections in which bacteria are present but are not actively dividing," notes
NIAID Director Anthony S. Fauci, M.D. "Dr. Barry and his colleagues
have now given us a detailed picture of how the candidate TB drug
PA-824 is metabolized inside Mycobacterium tuberculosis. Their
discovery is a promising step towards developing effective drugs
against latent TB as well as other bacteria."
Previously, Dr. Barry and his collaborators found that M. tb mutants
lacking a specific bacterial enzyme were resistant to PA-824, but
at that time, they did not know the function of the enzyme.
"It took several years, but at last we were able to recreate in
the test tube what happens inside mycobacterial cells when the
bacterial enzyme, which we named Ddn, and a second bacterial component
called a cofactor, interact with PA-824," says Dr. Barry. The key
event in PA-824 metabolism, they found, is the production of nitric
oxide (NO) gas. "This highly reactive molecule," he adds, "is akin
to a bomb blast that kills the bacteria from within."
NO gas is produced naturally by certain immune system cells after
they engulf M. tb or other bacteria. This is one way that people
with healthy immune systems can contain M. tb infection. However,
this natural immune response is not always enough to completely
rid the body of TB bacteria. In essence, PA-824 performs similarly
to the NO-producing immune cells — but the drug's effect is more
specific and triggered only after it enters the bacteria.
The non-dividing M. tb bacteria characteristic of latent TB infections
are walled off by immune cells that aggregate around the bacteria
to form a body called a granuloma. Oxygen levels are low inside
granulomas. In their latest research, the scientists observed that
NO-generation during PA-824 metabolism is greatest when oxygen
levels are low. This observation suggests how PA-824 may work against
non-dividing M. tb.
PA-824 was originally designed to work best under aerobic, or
oxygenated, conditions. With this new understanding of how the
bacterial enzyme and cofactor act on PA-824 under low-oxygen conditions,
Dr. Barry says, scientists can design drugs with a chemical structure
similar to PA-824 but optimize them from the start to behave best
under low-oxygen conditions. This work is already proceeding in
the laboratory at NIAID and in partnership with collaborators from
the Novartis Institute for Tropical Diseases in Singapore as well
as with scientists from the Genomics Institute of the Novartis
Research Foundation in San Diego.
Because humans have neither the bacterial cofactor nor any enzymes
equivalent to Ddn, PA-824 has no effect on human cells. Conversely,
many bacteria have enzymes in the same family as Ddn. Thus, says
Dr. Barry, it is possible to envision new kinds of NO-generating
drugs designed to interact with enzymes associated with other disease-causing
bacteria as well.
In addition to NIAID funding, this research received grant support
through the Grand Challenges in Global Health Program, which is
jointly funded by the Bill & Melinda Gates Foundation and the Wellcome
In 2000, Dr. Barry and colleagues at NIAID collaborated with the
Seattle-based firm PathoGenesis to publish the first description
of PA-824 (http://www3.niaid.nih.gov/news/newsreleases/2000/pa824.htm).
PA-824 entered human clinical trials in 2005 (http://www3.niaid.nih.gov/news/newsreleases/2005/tb_pa_824.htm).
The M. tb enzyme now named Ddn was first described by Dr. Barry
and his colleagues in 2005 http://www3.niaid.nih.gov/news/newsreleases/2005/tbdrug.htm.
For more information about Dr. Barry's research, see http://www3.niaid.nih.gov/labs/aboutlabs/lcid/tuberculosisResearchSection/barry.htm.
NIAID conducts and supports research — at NIH, throughout the United
States, and worldwide — to study the causes of infectious and immune-mediated
diseases, and to develop better means of preventing, diagnosing
and treating these illnesses. News releases, fact sheets and other
NIAID-related materials are available on the NIAID Web site at
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
R Singh et al. Bicyclic nitroimidazoles are intracellular NO donors and kill non-replicating Mycobacterium tuberculosis. Science DOI: 10.1126/science.1164571 (2008).