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New Medicine Is Best Hope Against Tuberculosis in 40 Years

A chemical compound that drug developers had shelved as a failed treatment for inflammation has unexpectedly become the most promising new tuberculosis medicine to emerge in 40 years, scientists said yesterday.

The surprise discovery that the drug is a potent antibiotic -- and one that in animals, at least, has many advantages over current TB drugs -- has generated a flurry of excitement among public health specialists struggling to control the growing global scourge.

Among infectious diseases, tuberculosis is the second leading cause of death worldwide, surpassed only by AIDS. Spread easily by coughing, the disease sickens more than 8 million people every year and kills 2 million to 3 million annually. Adding to the problem, a growing number of cases -- as many as 400,000 a year -- are caused by microbial strains that are resistant to currently used drugs.

The new compound, known simply as R207910, has been given to only 50 or so healthy people for safety testing so far. Studies of its effectiveness in people infected with TB will begin "very soon," said lead researcher Koen Andries of Johnson & Johnson Pharmaceutical Research & Development in Beerse, Belgium.

But in animal studies, described in today's issue of the journal Science, the compound easily overcame the two biggest hurdles facing TB therapies today: their ineffectiveness against resistant strains and the long period of treatment required to achieve a cure.

TB today is treated with a cocktail of three drugs that must be taken every day for six to nine months -- a daunting commitment that the majority of patients do not keep. When therapy is stopped prematurely, the disease recurs -- often in a form resistant to those drugs.

"The big problem in TB is not that we don't have drugs, it's that people are sick as hell and you give them drugs and after a month they feel good so they stop taking their drugs and they relapse," said Barry Bloom, dean of the Harvard School of Public Health. "Anything that shortens the time to kill off the TB bug would have a huge public health impact, even if it is not any better than other drugs."



In studies of mice infected with Mycobacterium tuberculosis, the slow-growing and difficult-to-kill bacterium that causes TB, the new compound lingered especially in the animals' lungs, where it is most needed, achieving concentrations 10 times higher than in the blood. When used with two of the three drugs commonly used today, R207910 cleared the animals' lungs of TB bacteria after just one month -- half the time needed to achieve that end with the standard three-drug-regimen in mice.

"That's a reason to be optimistic we would be able to shorten treatment duration [in people] by about 50 percent," Andries said.

Tuberculosis was the biggest infectious killer on Earth until AIDS erupted, though the distinction between the death tolls from those two diseases is somewhat artificial. More than 11 million people have both diseases, and TB plays a contributory role in at least 1 million AIDS deaths every year.

Happily, Andries said, the new compound has a particular advantage for those patients infected with both M. tuberculosis and the human immunodeficiency virus that causes AIDS. One of today's three standard TB drugs (the most modern of the three, rifampin, introduced in 1963) speeds the breakdown of several important AIDS drugs in the body, making simultaneous treatment for the two diseases difficult, but R207910 apparently does not.

R207910 is one of a new class of chemicals called diarylquinolines, several of which have been studied for their potential to block inflammation. A Johnson & Johnson scientist created R207910 by accident while trying to create a different diarylquinoline, Andries said, but it was saved for future study anyway.

When recent tests by the company indicated its potential against TB, the scientists there looked into how it works. They found that the compound throws a molecular monkey wrench into the cellular machinery by which the TB bacterium makes adenosine triphosphate, or ATP, the microbe's primary fuel.

That is a different killing mechanism than is found in any other antibiotic, and it explains why R207910 is just as effective against drug-resistant strains of M. tuberculosis as against conventional strains. Moreover, because the mechanism by which humans (and even most bacteria) make ATP is so different than that used by mycobacteria, the compound is expected to be very safe in people.

Volunteers had no significant side effects after taking a variety of doses over two weeks, Andries said, acknowledging that problems could arise with longer treatment.

The drug is not foolproof. Andries's team has already found that about one in every 200 million TB bacterium harbors a genetic mutation that allows it to live even in the presence of R207910. But that is a manageable level of resistance, experts said, as long as the new drug gets used in combination with others.

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said the new compound looks very promising but warned against raising hopes too soon. "I'm generally a little skeptical about things like this until you get into humans," he said.

Fauci also warned that TB drug development poses notoriously difficult financial challenges, both because human studies must be large to prove efficacy and because those countries that need it the most are least able to pay for it.

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