New Drugs May Drastically Shorten Tuberculosis Therapy

Three antibiotics that target the "switch region” of the bacterial RNA polymerase (RNAP) enzyme reportedly may reduce treatment of tuberculosis from six months to two weeks or less.

The three antibiotics are the alpha-pyrone antibiotic myxopyronin (Myx), the structurally related alpha-pyrone antibiotic corallopyronin (Cor), and the structurally unrelated macrocyclic-lactone antibiotic ripostatin (Rip). Data published in the October 17, 2008, issue of the journal Cell showed that all three drugs interacted with the RNAP "switch region”- the molecular hinge that mediates opening and closing of the RNAP active center cleft - to prevent interaction of RNAP with promoter DNA.

Investigators at Rutgers University (Piscataway, NJ, USA) used a combination of genetic, biochemical, and structural approaches to show that the three antibiotics bound to RNAP in a manner that was significantly different from that used by other currently used antibiotics such as the rifamycins. Since the new compounds operate differently, strains of tuberculosis and other bacteria that are resistant to rifamycins would not be resistant to them.

"RNA polymerase has a shape reminiscent of a crab claw, with two prominent pincer-like projections,” explained senior author Dr.Richard H. Ebright, professor of chemical biology at Rutgers University. "Just as with a real crab claw, one pincer stays fixed and one pincer moves - opening and closing to keep DNA in place. The pincer that moves does so by rotating about a hinge. Our studies show that the three antibiotics bind to and jam this hinge.”

The investigators anticipate that the new antibiotics would work much more efficiently against the tuberculosis bacteria than do the currently available drugs. "The Holy Grail in tuberculosis therapy is to reduce the course of therapy from six months to two weeks - to make treatment of tuberculosis like treatment of other bacterial infections,” said Dr. Ebright. "With a six-month course of therapy for a disease that is largely centered in the third world, the logistical problems of administering therapy over space and time make eradication a nonstarter. But, if there were a two-week course of therapy, the logistics would be manageable, and the disease could be eradicated.”

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