March 10, 2005
New Class of Tuberculosis-Fighting
Antibiotics Suggested By Biochemical-Pathway Study
(Philadelphia, PA) - A worldwide health problem, tuberculosis
kills more people than any other bacterial infection.
The World Health Organization estimates that two billion
people are infected with TB, and that two million people
die each year from the disease.
However, due to multi-drug resistance and a protracted
medication regimen, it is extremely difficult to treat.
Hence, there is still a great deal of interest in developing
new anti-tubercular drugs. Researchers at the University
of Pennsylvania School of Medicine have identified
a biochemical target that could lead to a new class
of antibiotics to fight TB. They report their findings
in this week’s online edition of the Proceedings
of the National Academy of Sciences .
In a proof-of-principle study, Harvey Rubin,
MD, PhD, Professor of Medicine, Division of
Infectious Diseases, and colleagues were able to stop
the bacteria from multiplying by inhibiting the first
step in a common biochemical pathway. This pathway is
responsible for making the energy molecules all cells
need to survive. First author Edward Weinstein,
an MD/PhD student, Rubin, and colleagues characterized
the pathway and showed that an important enzyme in it
is a key target for anti-TB agents.
The pathway, explains Rubin, is like a series of links
in a chain, with enzymes facilitating reactions along
the way. “We discovered that if you inhibit the
very first enzyme in the chain, you inhibit everything
else downstream and eventually the bacteria die,”
The research group tested phenothiazine, a drug used
in the past to treat schizophrenia, in cultures of Mycobacterium
tuberculosis, the bacterium that causes TB. They
found that phenothiazines killed the bacterium in culture
and suppressed its growth in mice with acute TB infection.
While the effect on the growth of TB in mice was small,
it suggested that a valid target was identified. The
research group went on to show that the enzyme disabled
by the phenothiazines is called type II NADH dehydrogenase
and is a unique and important antimicrobial target.
“What we have now is a new target in
TB,” says Rubin. “We’ve been able
to find at least the beginnings of a class of compounds
that we can start working with and that we know is biochemically
active against the TB bacteria in culture and in small
Is it a new drug for tuberculosis? Not yet, cautions
Rubin. It’s premature to say that this class of
drugs will cure TB, but it does represent the start
of basic research towards that, he concludes. Next steps
include more investigations on inhibitors of the NADH
biochemical pathway in TB, and the development of high-throughput
screens to find better and safer inhibitors of type
II NADH dehydrogenase.
This work was supported by grants from the National
Institutes of Health. Rubin and Weinstein’s coauthors
are Takahiro Yano, Lin-Sheng Li, David Avarbock, Andrew
Avarbock and Douglas Helm from Penn, and Andrew McColm,
Ken Duncan, and John T. Lonsdale from GlaxoSmithKline
(Collegeville, PA and Stevenage, UK). Animal studies
were conducted at GlaxoSmithKline. Penn researchers
report no conflicts of interest.
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