A chief reason that tuberculosis persists as a global killer--and is on the rise in parts of the world--is that existing antibiotics require up to 9 months of daily use, making it difficult for people to complete the treatment. Those who miss doses, in turn, fuel the emergence of drug-resistant strains of the mycobacterium that causes the illness. Yet the only new TB drugs to become available during the past 4 decades have been variations of the existing ones. Now researchers at Johnson & Johnson (J&J) in Belgium have discovered a compound that may dramatically reduce the amount of time it takes to cure the disease and that also appears to work against multidrug-resistant strains of Mycobacterium tuberculosis. "It's extraordinarily promising," says TB researcher and clinician Jacques Grosset of Johns Hopkins University in Baltimore.
As a team led by J&J's Koen Andries reports online 9 December in Science Express (www.sciencemag.org/cgi/content/abstract/1106753), extensive studies in the test tube and mice have shown that the compound, dubbed R207910, is more potent than existing drugs, stays in the body longer, and works by a novel mechanism that makes it broadly effective. Experiments in a small number of uninfected humans and toxicology studies in rats and dogs so far suggest that the compound is safe. "It's like a dream come true," says Andries, a microbiologist. "If you would make a wish list of the assets that an ideal TB compound would have," he says, this would be it.
Like the rest of the pharmaceutical industry, J&J has little financial incentive to develop treatments for TB, a disease that mainly afflicts the poor. But while screening for a new broad-spectrum antibiotic, J&J researchers stumbled upon the finding that a class of compounds called diarylquinolines worked against M. smegmatis, a cousin of TB. Chemical tinkering led them to the even more potent R207910. To date, the company has bankrolled development of the drug.
Andries's group has joined with outside research teams to conduct many of the experiments described in the current report. In particular, researchers in France provided a critical mouse model for TB, which led to the finding that the compound lasted unusually long in the rodent, suggesting that it might kill M. tuberculosis with fewer doses. The French researchers added the drug to the most popular triple combination now used--rifampin, isoniazid, and pyrazinamide--and found that it achieved the same bactericidal effects in half the time. Various combinations with two of the existing drugs also showed significant benefits.
As expected, resistance to R207910 developed when given to mice as a monotherapy, but the mouse data have convinced leading TB researchers that swapping the drug for one of the three in the current cocktail would delay development of resistant strains and would vastly shorten treatment. "This is quite frankly an astonishing set of results," says Denis Mitchison of St. George's Hospital Medical School in London. "They've managed with some of the combinations to get complete sterilization of organs within 2 months rather than 4. That's never been done before."
Mitchison (who consulted with J&J about the results) and several other researchers were particularly intrigued by the drug's novel mechanism of action. After sequencing the genomes of strains of M. tuberculosis and M. smegmatis that were resistant to R207910, Andries and his colleagues compared the results to the DNA from susceptible strains. The genetic mutations they discovered in the resistant strains all pointed to a gene that codes for an enzyme that makes ATP, which provides energy for cells. "Nobody before has identified that as a drug target for TB," says William Jacobs of the Albert Einstein School of Medicine in New York City.
Mel Spigelman of the Global Alliance for TB Drug Development, a nonprofit organization based in New York City that partners with industry and academics to accelerate R&D of faster-acting compounds, says R207910 is one of several novel agents now entering or nearing human trials (see chart). "There is a revolution in the development of drugs for TB," says Spigelman. Although R207910 has moved further than other novel drugs in the development pipeline, Spigelman predicts that several of the drugs will prove their worth in human tests. He imagines a day when combining the drugs now under development offers a therapy that cures the disease in as little as 1 week. He stresses, however, that the challenge is not simply developing new drugs but delivering them at an affordable price--a key mission of the alliance, which may work with J&J in the future.
J&J's Andries says the company understands that most of the 8 million people who suffer from TB each year cannot afford expensive new drugs. "What drives us most is the medical need for such compounds," says Andries, who adds that the lower rate of financial return could be offset by "goodwill toward the company." The drug will soon enter into trials in people who have active TB cases. Many promising drugs of course fail in human tests, notes Andries, but if all goes well, he says the compound could be on the market in 5 years.