A multi-institution collaboration between
The multi-institutional team exploited a chemical pathway that allows staph to defend itself against an immune response. The researchers showed that a compound called BPH-652 originally designed to lower cholesterol blocks a key enzyme in that pathway, weakening the staphs defenses and allowing the bodys immune cells to prevail against the infection.
A golden-colored pigment (aureus means golden in Latin) called a carotenoid gives the S. aureus bacterium its edge. The carotenoid acts as an antioxidant for the bacterium, allowing it to evade attack by the bodys immune cells. By crippling production of the carotenoid, the compound strips the staph of one of its key defenses.
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
The new research builds on a 2005 discovery by scientists at UCSD, led by Victor Nizet, MD, professor of pediatrics and pharmacy, and George Liu, MD, then a post-doctoral fellow at UCSD. That study showed that knocking out a gene for an enzyme in the chemical pathway that produced the staph carotenoid reduced its virulence.
When he read about this finding,
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, who is also affiliated with the Skaggs School of Pharmacy and Pharmaceutical Sciences at UCSD.
Preliminary studies were conducted in the laboratories of Nizet and Liu, now an assistant professor of pediatrics at
The key to the compounds success lies in the fact that the human and bacterial enzymes it targets are so similar.
Andrew Wang and his colleagues at Academia Sinica and the
The new findings are particularly promising because BPH-652 has already been explored as a cholesterol-lowering agent in human clinical trials. The existing knowledge of its properties may reduce the cost and time required for development of BPH-652 as an anti-infectious disease therapy, according to the researchers.
This research is an excellent example of how discoveries at the lab bench can lead to clinical advances, said Elias A. Zerhouni, MD, director of the National Institutes of Health (NIH), 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.
Additional contributors to the paper include Chia-I Liu and Wen-Yih Jeng, Academia Sinica,