Among the deadliest of all disease-causing organisms, Staph is the leading cause of human infections in the skin, soft tissues, bones, joints and bloodstream, and drug-resistant Staph infections are a growing threat. By federal estimates, more than 94,000 people develop serious MRSA infections and about 19,000 people die from MRSA in the U.S. every year. MRSA is believed to cause more deaths in the U.S. than HIV/AIDS.
The multi-institutional team exploited a chemical pathway that allows the Staph bacterium to defend itself against an immune response. The researchers showed that a compound (BPH-652) originally designed to lower cholesterol blocks a key enzyme in that pathway, weakening the organism’s defenses and allowing the body’s immune cells to prevail against the infection.A golden-colored pigment called a carotenoid gives the S. aureus bacterium its edge. “Aureus” is Latin for “golden.” The carotenoid acts as an antioxidant for the bacterium, allowing it to evade attack by the body’s immune cells. By crippling production of the carotenoid, the compound strips Staph of one of its key defenses.
When he read about this finding, University of Illinois chemistry professor Eric Oldfield realized that the chemical precursors of the Staph carotenoid were identical to those that led to production of cholesterol in humans. Oldfield, who is the senior author of the paper, had spent decades exploring this pathway, which has implications for the treatment of some cancers, as well as fungal and parasitic diseases. He noted that an enzyme in the human pathway, squalene synthase, was strikingly similar to one that led to the production of the carotenoid in Staph. He also knew that many compounds already had been developed to block the human enzyme.
“I thought there was a good chance that squalene synthase inhibitors developed early on as cholesterol lowering agents might also work on this other pathway,” he said. “Current cholesterol-lowering drugs like statins work in a completely different way and would be ineffective.”
The researchers began by testing dozens of new compounds for their activity against the Staph enzyme. This allowed them to narrow the field of potential candidates to eight. When they tested these drugs on Staph cells, they found that BPH-652 was the most effective at getting into the cells. A tiny dose impaired the cells’ ability to produce the carotenoid. The cells, once golden, turned white.
“We have found that the same golden armor used by Staph to thwart our immune system can also be its Achilles’ heel,” said Nizet, a study co-author, who is affiliated with the Skaggs School of Pharmacy and Pharmaceutical Sciences at UCSD.Preliminary studies were conducted in the laboratories of Nizet and Dr. George Liu, a professor of pediatrics at Cedar-Sinai Medical Center. Exposure to BPH-652 also markedly reduced bacterial levels in a mouse model of severe Staph infection.
“Our structural studies pinpointed how these drug candidates bound to the bacterial enzyme to shut off pigment production,” Wang said.
The new findings are particularly promising because BPH-652 already has been used (as a cholesterol-lowering agent) in human clinical trials, reducing the cost and time for development.
“This research is an excellent example of how discoveries at the lab bench can lead to clinical advances,” said Dr. Elias A. Zerhouni, the director of the National Institutes of Health, which supported the research. “By following their scientific instinct about a basic biological process, the researchers found a promising new strategy that could help us control a very timely and medically important health concern.”
Diana Yates | University of Illinois
Studying mitosis' structure to understand the inside of cancer cells
19.02.2018 | Biophysical Society
Calcium may play a role in the development of Parkinson's disease
19.02.2018 | University of Cambridge
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
19.02.2018 | Information Technology
19.02.2018 | Ecology, The Environment and Conservation
19.02.2018 | Life Sciences