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12 December 2013 1:00 pm ,
Vol. 342 ,
The iconic 125-year-old Lick Observatory on Mount Hamilton near San Jose, California, is facing the threat of closure...
Recent results from the Curiosity Mars rover have helped scientists formulate a plan for the next phase of its mission...
A new, remarkably powerful drug that cripples the hepatitis C virus (HCV) came to market last week, but it sells for $...
In pretoothbrush populations, gumlines would often be marred by a thick, visible crust of calcium phosphate, food...
Evolutionary biologists have long studied how the Mexican tetra, a drab fish that lives in rivers and creeks but has...
Victorian astronomers spent countless hours laboriously charting the positions of stars in the sky. Such sky mapping,...
In an ambitious project to study 1000 years of sickness and health, researchers are excavating the graveyard of the now...
Stefan Behnisch has won awards for designing science labs and other buildings that are smart, sustainable, and...
- 12 December 2013 1:00 pm , Vol. 342 , #6164
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The Staph Bug's Achilles' Heel
10 February 2011 5:31 pm
Staphylococcus aureus is a hard bug to kill. The bacterium is responsible for more U.S. deaths each year than HIV/AIDS, in part because it quickly develops resistance to antibiotics. Scientists have had a hard time figuring out how it ticks, but now researchers think they may have found a way to conquer S. aureus by blocking its ability to perform a critical task: recycling.
Recycling is so important that even bacteria do it. They chop up the RNA blueprints needed to design proteins and reassemble them into new instructions. Researchers have known for more than 20 years how so-called gram-negative bacteria like Escherichia coli degrade and recycle their RNA. But the process for gram-positive bacteria like S. aureus has remained unclear.
In the new study, researchers led by Paul Dunman, an infectious disease specialist at the University of Rochester in New York, identified genes that were more active when S. aureus was rapidly recycling RNA. Blocking the activity of a protein known as RnpA stopped the recycling, indicating that Dunman's team had found a key enzyme.
The discovery of RnpA is important, says Dunman, because it provides a new target for antibiotic development. If a bacterium couldn't recycle its RNA, two major problems would arise. For one, Dunman says, the bug would waste energy following outdated instructions and turning RNA into proteins it no longer needed. More important, it would run out of raw material with which to print its instructions, grinding everything in the cell to an abrupt halt. "If you can stop the enzymes involved in that process with a small molecule or chemical," says Dunman, "that chemical could be an antibiotic."
Toward that end, the team screened nearly 30,000 small molecules to identify compounds that inhibit the action of RnpA. The researchers found 14 that did the trick, but one molecule—named RNPA1000—was especially effective against S. aureus. RNPA1000 killed cells from all 12 major strains of methicillin-resistant S. aureus (MRSA), a major scourge of hospitals in the United States and elsewhere. It was also effective against strains of antibiotic-resistant, gram-positive Streptococcus pneumoniae, S. pyogenes, and Enterococcus faecium, which cause diseases from meningitis to cardiac infections.
The team showed that RNPA1000 can boost the potency of antibiotics already on the market, although they don't yet know how. The chemical also kills S. aureus biofilms, which are a common cause of infection on implanted catheters and other medical devices and are notoriously resistant to the actions of antibiotics.
The drug worked in mice, too. Half of S. aureus-infected mice recovered from their infections when treated with RNPA1000, whereas none of the untreated mice did, the team reports online today in PLoS Pathogens.
RNPA1000 did show some toxicity when applied at high doses in human cells, so Dunman's group is searching for compounds closely related to RNPA1000 that can still inhibit RnpA but without the toxic side effects.
What's more, says Dunman, bacteria will eventually develop resistance against any antibiotic, no matter how methodically selected. RNPA1000 is no exception, he says, "but the frequency [of resistance] in a laboratory setting is extremely, extremely low." This means that bacteria should develop resistance to RNPA1000 more slowly than other antibiotics.
Robert Daum, director of the MRSA Research Center at the University of Chicago in Illinois, calls the study "creative" and says it provides a new route to target the MRSA epidemic. "What's important about this to me is not necessarily that this very work might be the answer to the problem," he says, "but that we look at how this bug does its dirty work in patients and how can we stop that."