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.