16 October 2008
Scientists Discover Workings of New Class of Antibiotics
Compounds may prove effective at treating drug-resistant tuberculosis
Washington — Scientists have discovered how several novel compounds attack bacteria, paving the way for development of treatments against antibiotic-resistant tuberculosis, according to a study published in the journal Cell on October 17.
More than 2 billion people are infected with the bacteria that cause tuberculosis, and an estimated 1.5 million die from it annually, according to the World Health Organization. Infections can be treated with a six-month course of antibiotics, but drug-resistant tuberculosis strains have emerged as a major challenge to treatment.
The new study focused on three compounds — myxopyronin, corallopyronin and ripostatin — and demonstrated that they attack a different site within bacteria than do antibiotics now used to treat infections. Bacteria have not yet evolved a way to defend against this unique attack mechanism, making these compounds promising candidates in the fight against antibiotic-resistant tuberculosis.
“For six decades, antibiotics have been our bulwark against bacterial infectious diseases,” said Richard Ebright, a professor in the Department of Chemistry at Rutgers University in New Jersey and a lead study author. “Now, this bulwark is collapsing. There is an urgent need for new antibiotic compounds and practical new targets.”
American and Indian scientists at Rutgers and researchers at the Helmholtz Centre for Infection Research in Braunschweig, Germany, collaborated on the research.
OVERCOMING ANTIBIOTIC RESISTANCE
A battlefield adage — if you build a better sword your enemy will build a better shield — applies to scientists’ war against disease-causing bacteria. New antibiotics may be effective initially, but, inevitably, strains of bacteria evolve that are resistant to a particular antibiotic.
The rate at which resistance develops is a function of how responsibly treatment is administered. For example, combination therapy — simultaneous treatment with multiple compounds that attack different targets — decreases the rate at which resistant strains evolve, Ebright told America.gov.
One frontline anti-tuberculosis agent, rifampicin (also called rifampin), attaches to an essential bacterial protein called RNA polymerase (RNAP) and prevents it from functioning, killing the bacterium. Rifampicin is particularly effective because it kills the slow- and fast-growing tuberculosis variants.
In the case of rifampicin-resistant tuberculosis, the bacteria develop mutations that prevent rifampicin from binding to RNAP. Such strains remain infectious and cause disease but are resistant to treatment.
More than 10 years ago, study co-authors Rolf Jansen and Herbert Irschik identified the antibiotics myxopyronin, corallopyronin and ripostatin from soil microbes and showed that they kill tuberculosis bacteria by attacking RNAP.
Hundreds of antibiotic compounds have been similarly identified, but without understanding how these chemicals attack bacteria it is nearly impossible to choose which to develop for use in treating infections.
TARGETING BACTERIAL PROTEINS
RNAP is shaped like a crab claw. The claw opens and closes to grab DNA and assemble RNA, the first step in synthesizing proteins.
“Just as with a real crab claw, one pincer stays fixed and one pincer moves — opening and closing to keep DNA in place,” Ebright said. “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, one of the study’s leaders, referring to this hinge. “It’s a drug designer’s dream because it’s a pocket that can accommodate a variety of chemical inhibitors.”
Rifampicin binds a different region of the claw than does myxopyronin, which explains why tuberculosis strains that are resistant to rifampicin are susceptible to myxopyronin.
Every cell, from those in bacteria to those in humans, needs proteins to function and uses some version of RNAP to produce them. The specific part of the claw’s hinge where myxopyronin binds is different in humans and bacteria, suggesting that myxopyronin will not impair the human version of RNAP. Because bacterial RNAPs are similar to one another, myxopyronin could be effective against many types of bacteria.
Now that researchers understand how myxopyronin works, Ebright and his colleagues are synthesizing more potent myxopyronin derivatives that potentially can be used as part of a combination therapy against antibiotic-resistant tuberculosis.
Already they have identified 12 compounds that are more potent than myxopyronin and nontoxic in laboratory animals, with dozens more remaining to be characterized. Ebright estimates that it will take about two years to identify the most effective compound. If this occurs, clinical trials could begin in five years.
For more information on U.S. efforts to fight tuberculosis, see “U.S. Increases Funds for Combating Drug-Resistant Tuberculosis.”
