New compound overcomes drug-resistant Staph infection in mice

Chemistry professor Eric Oldfield (in blue, center), graduate student Wei Zhu (left), research scientist Yonghui Zhang, University of Illinois, and their colleagues at UC San Diego discovered a compound that cured drug-resistant Staphylococcus aureus infection in mice. Credit: L. Brian Stauffer

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 . The team discovered and developed several 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- 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 to look for potential chinks in the armor of a known as FPPS that aids in 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 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 will emerge.

More information: This paper first appeared online on Dec. 17, 2012. The paper is in the Jan. 2, 2013 issue of PNAS.

Related Stories

Modified bone drug kills malaria parasite in mice

Feb 27, 2012

A chemically altered osteoporosis drug may be useful in fighting malaria, researchers report in a new study. Unlike similar compounds tested against other parasitic protozoa, the drug readily crosses into ...

Additive restores antibiotic effectiveness against MRSA

Oct 22, 2012

Researchers from North Carolina State University have increased the potency of a compound that reactivates antibiotics against methicillin-resistant Staphylococcus aureus (MRSA), an antibiotic-resistant form of Staphylococcus that is notor ...

Researchers analyze how new anti-MRSA abtibiotics function

Jul 28, 2008

A new paper by Shahriar Mobashery, Navari Family Professor in Life Sciences at the University of Notre Dame, and researchers in his lab provides important insights into promising new antibiotics aimed at combating MRSA.

Recommended for you

Student seeks to improve pneumonia vaccines

20 hours ago

Almost a million Americans fall ill with pneumonia each year. Nearly half of these cases require hospitalization, and 5-7 percent are fatal. Current vaccines provide protection against some strains of the ...

Seabed solution for cold sores

22 hours ago

The blue blood of abalone, a seabed delicacy could be used to combat common cold sores and related herpes virus following breakthrough research at the University of Sydney.

Better living through mitochondrial derived vesicles

Aug 19, 2014

(Medical Xpress)—As principal transformers of bacteria, organelles, synapses, and cells, vesicles might be said to be the stuff of life. One need look no further than the rapid rise to prominence of The ...

Zebrafish help to unravel Alzheimer's disease

Aug 19, 2014

New fundamental knowledge about the regulation of stem cells in the nerve tissue of zebrafish embryos results in surprising insights into neurodegenerative disease processes in the human brain. A new study by scientists at ...

User comments

Adjust slider to filter visible comments by rank

Display comments: newest first

tekram
not rated yet Jan 07, 2013
Don't forget to mention William Sinko who contributed equally to this work. The total synthesis is also described:
http://www.pnas.o...lemental
N4, N4′-Bis(3-(4,5-Dihydro-1H-Imidazol-2-yl)Phenyl)-[1,1′-Biphenyl]-4,4′-Dicarboxamide (17)