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New Drugs Hold Promise Against Drug-Resistant TB

Tuberculosis (TB) is the world's oldest known infectious disease and the one that kills the most people today, about two million a year. Yet, no new TB drugs have been introduced in nearly 40 years. That could change, however, with several promising new compounds expected to undergo human trials soon.

The urgency to develop new tuberculosis drugs grows as strains that resist the current medications spread across the globe. The World Health Organization estimates that 300,000 cases of multi-drug resistant TB emerge each year, enhanced by the parallel spread of HIV, which weakens immune systems and encourages other diseases.

New drugs showing early promise against the TB scourge in animal and human tests have been the highlight of two recent international conferences. At the annual meetings of the International Union Against Tuberculosis and Lung Disease in Paris and the American Society of Microbiology in Washington, researchers presented data about powerful experimental compounds they hope will dramatically cut TB treatment time from nine to two months.

"It really is a remarkable achievement over the last two or three years that we've seen a pipeline of [the first] new, potential candidates of TB drugs since the 1960s," says Dr. Maria Freire, the President of the Global Alliance for TB Drug Development.

"In general, I think the sense in the tuberculosis community is one of cautious optimism," she adds. "Anyone who has developed medicines knows that there is a very large attrition rate, but the fact that we have important compounds -- we can't but not only be pleased, but express cautious optimism for the work the scientists are doing all over the world."

The TB alliance Dr. Freire leads is a major reason new drugs against the lung disease are coming along. The non-governmental group was launched in 2000 in Bangkok with the goal of supporting the development of affordable drugs that shorten the treatment course, are effective against drug-resistant strains, and work against latent TB infections, which affect one-third of the world's population. It, in turn, is supported by donor nations and charitable agencies.

"Our mission is to try and reinvigorate the field and support drug development for TB that allows others to, in fact, join us in this goal," says Dr. Freire.

All of the eagerly awaited TB compounds meet the TB Alliance's goal of being effective against drug resistant strains, at least in the test tube and animal experiments. The drugs attack different targets in the germ.

Two are novel compounds shown to be as potent as first-line TB drugs. One developed by the U.S. pharmaceutical firm Johnson and Johnson remains in the body for long periods, meaning the possibility of less frequent doses. The company believes that if it can be added to the treatment regimen, it would shorten the duration. The other has been developed by the multinational drug giant Chiron. Both are expected to begin human testing early next year.

The Swiss drug giant Novartis, a Chiron partner, is seeking a more potent version of the Chiron compound, called PA-824, to improve its ability to kill non-replicating TB. Conventional drugs work only when TB is duplicating, but Novartis chemist Thomas Keller says it is important to attack the widespread latent form to prevent it from becoming active.

"Since PA-824 looks so promising, we felt it was important to look for second generation molecules," he said. "Especially important is we want to have enhanced activity against non-replicating bacteria. This is a property we believe is really unique for PA-824, so we want to enhance this property in al follow-up."

Researchers are also screening existing antibiotics to see if variants work against TB. The Maryland biotechnology firm Sequella says its lead compound is based on the first-line drug ethambutol, but is structurally different, which gives it an advantage in confounding drug resistant strains accustomed to the current drug. It, too, is headed for human trials early next year.

University of Illinois researchers are experimenting with derivatives of the standard antibiotic erythromycin, used against bacterial infections such as pneumonia, diphtheria, whooping cough, and gonorrhea. The scientists acquired 30 related compounds ignored by the drug industry and found them to be highly potent against all forms of TB.

The Global TB Alliance's research director, Dr. Mel Spigelman voices optimism about the future of tuberculosis treatment.

"Having now almost the plethora of new drugs to begin to develop clinically is really an amazing change in the world of TB," adds Dr. Spigelman.

As Sequella's Carol Nacy puts it, the notion that drug companies are no longer interested in tuberculosis can be dismissed.