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
Not of Divided Mind
19.01.2017 | Hertie-Institut für klinische Hirnforschung (HIH)
CRISPR meets single-cell sequencing in new screening method
19.01.2017 | CeMM Forschungszentrum für Molekulare Medizin der Österreichischen Akademie der Wissenschaften
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
19.01.2017 | Earth Sciences
19.01.2017 | Life Sciences
19.01.2017 | Physics and Astronomy