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.
The National Institutes of Health, National Science Foundation and Howard Hughes Medical Institute supported this research.Editor’s note: To reach Eric Oldfield, call 217-333-3374;
Diana Yates | University of Illinois
Further reports about: > HIV/AIDS > MRSA > Methicillin-Resistant Staphylococcus aureus > Science TV > Staph > UPPS > antibacterial drug development > antibiotic-resistant bacterial infections > bacterial cell > bacterial infection > cell wall biosynthesis > computer simulation > dangerous bacterial infection > drug resistance > drug-resistant S. aureus > multiple enzymes
The birth of a new protein
20.10.2017 | University of Arizona
Building New Moss Factories
20.10.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Information Technology
20.10.2017 | Materials Sciences
20.10.2017 | Interdisciplinary Research