Apr. 7, 2005 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,” he explains.
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 animals.”
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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