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Researchers Search for New Weapons in Fight Against TB

Tuberculosis, often thought of as a relic of a pre-antibiotic era, is alive and well – more than one-third of the world’s population is infected with the bacteria, and more than one-fifth of those infected will develop the disease. Meanwhile, the antibiotics used to treat TB are losing their power as strains develop that are resistant to every known antibiotic.

Now, researchers have discovered that three naturally-occurring antibacterial compounds may provide a basis for a new class of antibiotics to treat tuberculosis and other infections, according to a study published this week in the journal Cell

Bacteria naturally secrete the compounds – myxopyronin, corallopyronin and ripostatin – as part of their “chemical warfare” against other bacteria. In the study, researchers found that the compounds work by “jamming” an enzyme called RNA polymerase that’s essential to bacteria’s growth – it transcribes the genetic instructions in DNA into RNA, which then directs protein assembly.

Part of the enzyme is shaped like a crab’s claw, with a hinged pincer that opens and shuts to grab strands of DNA, says study author Richard Ebright, a microbiologist at the Howard Hughes Medical Institute.

“What we found is that all three of these agents function by binding to that hinge region,” Ebright explains. “They trap the hinge in a closed position, so it’s unable to open up.”

The compounds are particularly promising, Ebright says, because researchers already know that RNA polymerase is a good target for TB drugs. In a TB infection, he explains, there are both quickly-growing, active bacteria and slowly-growing, dormant bacteria. To eliminate the infection, a drug must target both types. However, there are very few cellular processes occurring in the dormant bacteria, so there are few processes to interfere with -the RNA polymerase process is one of those few.

One of the most effective current TB antibiotics, rifamicin, already targets RNA polymerase; however, it targets a different part of the enzyme. That means that TB strains that are already resistant to rifamicin wouldn’t be resistant to the potential new drugs. It also means that the new drugs could be administered together with rifamicin.

“RNA polymerase is one of the best targets for treatment of TB,” says Zhenkun Ma, head of research at the nonprofit Global Alliance for TB Drug Development. “This may finally open a totally new approach, still using that target.”

The potential drugs could also be useful against a range of other bacterial infections, Ebright says, because all bacteria species have the same target hinge area of RNA polymerase.

“[The compounds] have a broad spectrum of activity,” Ebright says, “and they have a special unique importance for TB.”

Steven Hughes, director of the HIV drug resistance program at the National Cancer Institute, says that there’s good reason to be excited about the possible new class of antibiotics.

“This is something that comes along on the interval of years, not months or days,” he says. However, he cautions that it’s important to understand that the compounds, while promising, are not yet drugs.

“These are inhibitors, they are the fathers or grandfathers of drugs,” he says. “There will need to be additional work.”

First, for example, researchers will need to develop versions of the compounds that are more potent – that work against bacteria at lower concentrations.

Ebright says that he expects to have drugs ready for clinical trials within the next three to four years.

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