Thanks to a barroom conversation, researchers may have stumbled on a powerful drug combination to battle antibiotic-resistant tuberculosis (TB), a growing threat throughout the world. New work suggests that meropenem and clavulanate, both of which are approved by the U.S. Food and Drug Administration to fight bacterial infections, tame some of the most virulent TB strains.
An increasing number of people have multidrug-resistant (MDR) strains of Mycobacterium tuberculosis, which causes tuberculosis. Last year, the World Health Organization reported the highest number of cases ever--about half a million--and pinpointed the countries of the former Soviet Union and China as the hardest hit. Currently, MDR-TB patients must take expensive, highly toxic treatments for as long as 2 years to cure their infections. And since 2006, researchers have found that about 10% of these people actually have "extensively drug-resistant" (XDR) strains that can outmaneuver nearly all known treatments. MDR-TB has a fatality rate of more than 50%, and XDR-TB is deadlier still--especially when combined with HIV infections, a severe problem in several southern African countries.
But in today's issue of Science, a group led by biochemist John Blanchard of the Albert Einstein College of Medicine in New York City reports test-tube evidence that, when used in tandem, meropenem and clavulanate worked against all 13 strains of XDR-TB they tested. Although some researchers expressed surprise that Science accepted an in vitro drug study without any animal or human data, Blanchard stresses that the urgency of the problem and the availability of these drugs raises the importance of their findings.
Blanchard says the idea dates back to a meeting he had in a Paris bar 3 years ago with a French graduate student, Jean-Emmanel Hugonnet, who wanted to work in his lab on fundamental questions about enzyme kinetics. "This was not planned as a drug-discovery program," says Blanchard. Hugonnet had been working in a Paris lab with the enzyme β-lactamase, which is made by M. tuberculosis and other bacteria and has a murky function; and they decided to make that the center of his studies. The enzyme is important because it cripples a class of antibiotics called β-lactams, which includes penicillin and a newer drug called meropenem that's commonly used to treat pneumonia and meningitis.
But what if there was a way to inhibit β-lactamase so that drugs like meropenem could work their magic? Blanchard knew that an older drug called clavulanate, which shuts down the enzyme, was used just that way to help the β-lactam amoxicillin treat everything from ear aches to urinary tract infections. (Indeed, one earlier study in TB patients of that combo showed that it had some activity against the bug.) So he and colleagues decided to combine clavulanate with various β-lactams and test them against various M. tuberculosis strains. "Once you knock out β-lactamase chemically, bam, these other compounds have effects," says Blanchard. The combination of clavulanate and meropenem performed the best, the team reports, with tiny concentrations of the β-lactam killing every M. tuberculosis culture the team tested.
"I'm highly excited about it," says microbiologist Willem Sturm of the Nelson Mandela School of Medicine in Durban, South Africa, who has recently confronted a large outbreak of XDR-TB there. "But we really need to see whether they do what the in vitro experiments promise." To that end, Sturm hopes to launch a clinical study in South Africa later this year with Brian Currie, an infectious-disease physician at Albert Einstein. The study will test the drugs in people who are doubly infected with HIV and MDR or XDR strains of M. tuberculosis. Researchers from the U.S. National Institute of Allergy and Infectious Diseases also have plans for a second trial with colleagues in South Korea to test the antibiotics in drug-resistant TB patients who are not infected with HIV.
A few other compounds to combat XDR-TB are in clinical trials, but they still must pass safety hurdles--let alone proof of efficacy--that meropenem and clavulanate have already cleared. According to the Global Alliance for TB Drug Development, none of these studies is likely to be completed until at least 2012.