New Treatment Strategy for Serious "Staph" Infections
A multi-institution collaboration between U.S. and Taiwanese scientists, including researchers at the University of California, San Diego (UCSD) School of Medicine
and the Skaggs School of Pharmacy and Pharmaceutical Sciences, has
uncovered a completely new treatment strategy for serious
Staphylococcus aureus ("Staph") infections. The research, published
Feb. 14 in the online version of the journal Science (ScienceXpress),
comes at a time when strains of antibiotic-resistant Staph (known as
MRSA, for methicillin-resistant S. aureus) are spreading in epidemic
proportions in both hospital and community settings.
multi-institutional team exploited a chemical pathway that allows the
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
Staph's defenses and allowing the body's 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 body's immune cells. By crippling production of the
carotenoid, the compound strips the Staph of one of its key defenses.
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 United States every year.
research builds on a 2005 discovery by scientists at UCSD, led by
Victor Nizet, MD, professor of pediatrics and pharmacy, and George Liu,
M.D., 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, 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 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 had already been developed to block the human enzyme.
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."
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.
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 Cedar-Sinai Medical Center in Los Angeles. Exposure to BPH-652 also markedly reduced bacterial levels in a mouse model of severe Staph infection. The key to the compound's 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 National Taiwan University used X-ray crystallography to determine the structure of the enzyme and how it interacts with the inhibitors. "Our
structural studies pinpointed how these drug candidates bound to the
bacterial enzyme to shut off pigment production," Wang said.
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.
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."