Killing TB While it Sleeps

Newly discovered compounds can kill tuberculosis bacteria while it is in its dormant state.

October 28, 2009

Scientists have discovered compounds that block a specific process inside tuberculosis-causing bacteria and can kill off the microbe while it is in its dormant state, according to a new study. The compounds could help researchers develop new anti-tuberculosis drugs.

Tuberculosis, or TB, infects about one-third of the global population, or 2 billion people, and claims the lives of close to 2 million people annually. In the majority of cases, the bacteria are suppressed by the immune system and do not replicate. Instead they lie dormant, hibernating inside the patient’s cells. Only about 10 percent of these cases turn into active infections, but it is important to treat latent TB in certain groups of people that are at high risk for developing the full-blown disease, such as immunocompromised individuals, those with HIV/AIDS and children.

Most antibiotics against non-replicating TB work by preventing the bacteria from building essential proteins, such as those found in its cell wall – an outer layer that protects the microbe against immune attack. But researchers from Weill Cornell Medical College, Brookhaven National Laboratory and Rockefeller University in New York attempted to attack the dormant microbe using a new strategy – blocking protein breakdown.

A unique feature of tuberculosis is that it is the only bacterium to have a proteasome: a structure inside the cell that removes damaged proteins and helps the bacteria survive in the dormant state. The researchers thought that if they could specifically target the proteasome and stop it from working, damaged proteins would accumulate inside the bacteria and cause the microbe’s death.

The team screened 20,000 compounds and identified a group of related compounds, called “oxathiazol-2-one,” that could effectively block the proteasome activity. They then tested the inhibitors on TB bacteria and on monkey and human cells. They found that the inhibitors killed the TB bacteria, but they did not appear to harm mammalian cells, which also have proteasomes.

The researchers also saw that oxathiazol-2-one inhibited the TB proteasome about 1,000 times more effectively than the human proteasome.

The study, which was led by Carl Nathan of Weill Cornell, is the first to find compounds that kill bacteria by blocking the degradation, rather than the synthesis, of proteins. The work establishes the concept that targeting protein degradation could be the basis for developing antibiotics, said Gang Lin, a researcher at Weill Cornell and a co-author of the paper, which was published online in the journal Nature on September 16.

“I think its very promising,” Dr. Joel Ernst, a professor of microbiology and director of the Division of Infectious Disease at New York University’s School of Medicine, said of the work. “I find it appealing that there’s a TB specific drug target.” Ernst was not involved in the Nature study.

Currently, treating latent TB requires nine months of drug therapy – a lengthy process that can lead to antibiotic resistance if the patient stops taking the medication. Because of these drawbacks, researchers would like to find more effective treatments for the disease, which may arise through new approaches to attacking the bacteria, such as the one presented in the current study.

“People fantasize about being able to treat TB for just two or three weeks and being able to cure it,” said Ernst. “That’s a fantasy right now, but drugs that appear to attack targets that the bacteria need to survive even though they’re not all replicating would be a real breakthrough.”

The researchers plan to learn more about how these compounds block TB proteasomes so that they can design inhibitors that are even more specific, according to Lin. They also hope to test the compounds on experimental animals.

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