Researchers reveal new drug possibilities in the battle against tuberculosis

by Nicky Penttila

July 6, 2007

By taking a deeper look into the structure of the bacteria that causes tuberculosis, scientists have found a new target in the battle to stop it.

Using x-ray crystallography, researchers in Switzerland have defined the atomic structure of an important connection in the development of tuberculosis infection for the first time. With such an atomic blueprint, drug makers may have a new target for one of the world's deadliest diseases.

Nearly 1.6 million people worldwide die of tuberculosis (TB) each year, according to the World Health Organization. One reason TB is so deadly is that the immune system does not always recognize it, so does not know to stop it. Mycobacterium tuberculosis, the bacteria that causes TB, can "hide" inside the cell--inside the macrophages, which are the very cells that should be destroying them.

In 2004, scientists showed they could block the action of the M. tuberculosis "cloaking" enzyme, PknG, by introducing a chemical compound, AX20017, into the cell.  In the Proceedings of the National Academy of Science this week, Nicole Scherr and colleagues described exactly how that interaction works--the crystal structure of PknG, AX20017 and the connection between them.

"We can now start to think of rationally designing molecules" that could work in test tubes and in living beings, wrote Jean Pieters, the lead author of the study, in an e-mail. "The goal now is to develop this compound [AX20017] into a drug." This new class of drugs would block the enzyme, which would allow an infected person's innate defenses to kill the bacteria.

In the paper published this week online in the Proceedings of the National Academy of Sciences, researchers also report that this connection is quite specific—the compound does not target the 10 other similar enzymes (called kinases) in M. tuberculosis, nor likely most of the other 500 or so known human kinases. The target enzyme, PknG, has been found only in disease-causing strains of mycobacteria (the bacteria family that includes TB), so attacking it would presumably not harm healthy body functions.

The atomic-scale video of the interaction between the two shows AX20017 inserted deep inside a groove of the PknG enzyme like a ball in a catcher's mitt [video links near the bottom of the page].

There are effective, if multi-stage, drug therapies for most forms of TB, though the number of cases of increasingly drug-resistant TB continues to grow. About 8.8 million people each year develop TB; about 450,000 each year develop a form of the disease that is resistant to one or more of the drugs used to combat it, and an estimated 30,000 develop a form resistant to nearly all antibiotics, according to the World Health Organization. No new drugs to combat TB have come onto the market for more than 40 years, according to a review in The Lancet in 2006.