Researchers have discovered a new compound that restores the health of mice infected with methicillin-resistant Staphylococcus aureus (MRSA), an otherwise dangerous bacterial infection. The new compound targets an enzyme not found in human cells but which is essential to bacterial survival.
The research team, led by scientists at the University of Illinois and the University of California, San Diego, reports the new findings in the Proceedings of the National Academy of Sciences. The team discovered and developed several compounds that are promising leads for antibacterial drug development, and the most potent was tested in mice infected with MRSA.
The rise of antibiotic-resistant bacterial infections is a global public health problem, said U. of I. chemistry professor Eric Oldfield, who led the research with UC San Diego professor Andrew McCammon.
"There's an urgent need for more antibiotics because of drug resistance," Oldfield said. "There are, for example, completely drug-resistant strains of tuberculosis. None of the drugs work against these strains of tuberculosis and so, if you get it, you die."
Other infections, such as gonorrhea, which once were easily cured with antibiotics, also are becoming resistant to treatment, Oldfield said. "And Staph itself actually kills more people in the U.S. than does HIV/AIDS."
To begin the study, McCammon and his colleagues at UC San Diego used computer simulations to look for potential chinks in the armor of a bacterial enzyme known as FPPS that aids in bacterial cell wall formation. The researchers then screened libraries of small molecules to identify some that might target those sites and interrupt the activity of FPPS. Oldfield's team tested some of these molecules against FPPS, but found that they were not particularly potent inhibitors of the enzyme.
"Then we tested the most promising compound against the next enzyme in the pathway, and we found that it was 20 times more active against that enzyme," Oldfield said.
That enzyme, called UPPS, "is important because it's involved in bacterial cell wall biosynthesis," he said. "And a lot of the antibiotics that we have – drugs like penicillin, methicillin, vancomycin – all target bacterial cell wall biosynthesis."
Graduate student Wei Zhu and research scientist Yonghui Zhang worked with Oldfield to develop and test new analogs of the compound that worked against UPPS.
"And we found one that was about 1,000 times more active than the first hit we had against FPPS," Oldfield said.
Illinois chemistry and Institute for Genomic Biology professor Douglas Mitchell tested the new compound against regular and drug-resistant S. aureus in cell culture and found that it had potent activity against both.
"He also found that it augmented the effects of methicillin" in methicillin-resistant Staph strains, Oldfield said.
In a final test, Dr. Victor Nizet at UC San Diego used the new compound to treat mice infected with MRSA.
"Twenty out of 20 animals survived if they were treated with this drug lead and zero survived if they weren't treated," Oldfield said.
More years of study will be needed to determine whether this compound or others like it will be effective in humans, Oldfield said, but the findings may allow scientists to target multiple enzymes essential to bacterial survival, thus reducing the likelihood that new forms of drug resistance will emerge.
University of Illinois at Urbana-Champaign: http://www.uiuc.edu
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
About once a year, Florida harvester ants dig new nests, a mystery entomologists are eager to get to the bottom of.
The finding that male homosexuality has a strong genetic component should be a boon for gay rights – but it could backfire
Alan Turing, the man who pioneered computing, also forced the world to question what it means to be human
During sleep, the brain locks in existing memories and can even form new ones. Scientists say they are starting to understand how that happens. A midnight snack may interfere.
They walk among us. Natural experiments, living ordinary lives, unaware that their genes may hold the clue to the next superdrug.
A crowd at the Santa Barbara Zoo got a pleasant surprise when its latest star attraction, a baby giraffe, came out for a jaunt
A massive white matter tract at the back of the brain, overlooked for the past century, might be crucial for skills such as reading.
An award-winning book on optical illusions explains the science of tricking your brain.
Scientists investigating a huge die-off of starfish along North America's Pacific coast have identified a virus they say is responsible for a calamitous wasting disease that has wiped out millions of the creatures since it first appeared last year.
After 43,000 years in the Siberian permafrost, the remains of a mammoth may contain enough DNA to recreate the beast's genome