New class of antibiotics may lead to therapy for drug-resistant tuberculosis

Researchers are hot on the trail of a whole new class of broad-spectrum antibiotics, according to a new report in the October 17th issue of the journal Cell, a Cell Press publication.

The discovery holds promise at a time when a quarter of all deaths worldwide are the result of bacterial infectious diseases, and yet more and more disease-causing bacteria are growing resistant to currently available antibiotics. What’s more, the antibiotics under study in this report may offer a more effective and shorter course of treatment for tuberculosis (TB), a disease that is carried by one in three people in the world and that is particularly difficult to treat with today’s antibiotics.

“For six decades, antibiotics have been our bulwark against bacterial infectious diseases,” said Richard Ebright, a Howard Hughes Institute investigator at Rutgers University. “Now, this bulwark is collapsing. There is an urgent need for new antibiotic compounds and practical new targets.”

The team has now discovered how three antibiotic compounds—all of which are natural products produced by certain bacteria for use in a kind of chemical warfare against other bacteria —work to kill bacteria. The finding sets the stage for developing even more effective and specific compounds, a challenge the researchers already have well underway.

For all major bacterial pathogens, strains resistant to at least one current antibiotic have arisen, Ebright said. For several bacterial pathogens, including tuberculosis, there are strains resistant to all current antibiotics. Bacterial pathogens relevant to bioterrorism can be intentionally engineered—and, in the former USSR, were intentionally engineered—to resist to all current antibiotics, he noted.

In the new study, the researchers examined three antibiotic compounds, called myxopyronin, corallopyronin, and ripostatin, that block the action of RNA polymerase specifically in bacteria. RNA polymerase is an essential protein in all organisms and is required to transcribe the genetic instructions in DNA into RNA, which in turn directs the assembly of proteins.

“RNA polymerase has a shape reminiscent of a crab claw, with two prominent pincer-like projections,” Ebright said. “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.”

“It’s an amazing site,” added Eddy Arnold, also of Rutgers University, of this hinge that the researchers refer to as a switch region. “It’s a drug designer’s dream because it’s a pocket that can accommodate a variety of chemical inhibitors.” Two of the antibiotic compounds, myxopyronin and corallopyronin, have “good features” against a broad range of infectious diseases including TB, according to the researchers. While an existing class of drugs now used as a first-line against TB known as rifamycins also act on RNA polymerase, they do it in a different way, they explained.

Because the new compounds operate differently, strains of TB and other bacteria that are resistant to rifamycins would not be resistant to them.

Even when rifamycins are effective, they require six to nine months of therapy, Ebright said. For those who can’t tolerate those drugs or who carry a strain of TB that is resistant to them, the duration of therapy can go on for two years.

The researchers said that antibiotics targeting this RNA polymerase hinge may yield a much shorter course of TB therapy.

“The Holy Grail in TB therapy is to reduce the course of therapy from six months to two weeks – to make treatment of TB like treatment of other bacterial infections,” Ebright said. “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.”

Two of the naturally occurring compounds now examined may offer new drugs in their own right, the researchers said. Using the detailed information they’ve gathered about how those compounds bind and block RNA polymerase, they are also modifying those compounds in search of ones that might meet their ultimate goal: a two-week TB regimen.

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The researchers include Jayanta Mukhopadhyay, Howard Hughes Medical Institute, Rutgers University, Piscataway, NJ; Kalyan Das, Rutgers University, Piscataway, NJ; Sajida Ismail, Howard Hughes Medical Institute, Rutgers University, Piscataway, NJ; David Koppstein, Howard Hughes Medical Institute, Rutgers University, Piscataway, NJ; Minyoung Jang, Howard Hughes Medical Institute, Rutgers University, Piscataway, NJ; Brian Hudson, Rutgers University, Piscataway, NJ; Stefan Sarafianos, Rutgers University, Piscataway, NJ; Steven Tuske, Rutgers University, Piscataway, NJ; Jay Patel, Rutgers University, Piscataway, NJ; Rolf Jansen, Helmholtz Centre for Infection Research, Braunschweig, Germany; Herbert Irschik, Helmholtz Centre for Infection Research, Braunschweig, Germany; Eddy Arnold, Rutgers University, Piscataway, NJ; and Richard H. Ebright, Howard Hughes Medical Institute, Rutgers University, Piscataway, NJ.

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