(Taiwan) Cholesterol-lowering drug is effective against staphylococcus aureus :: BiotechEast - Taiwan and China biotechnology, medical devices, pharmaceuticals, ^¤å½s×, ^¤å×§ï ::

(Press release, Academia Sinica)

18 February, 2007
A multi-institution collaboration between US and Taiwanese scientists has uncovered a completely new treatment strategy for serious Staphylococcus aureus infections. The research, published Feb. 14, 2008, in the online version of Science magazine, comes at a time when strains of antibiotic-resistant Staph known as MRSA (methicillin-resistant Staphylococcus aureus) are spreading in epidemic proportions in both hospital and community settings.

Among the deadliest of all disease-causing organisms, Staph is the leading cause of human infections in the skin and soft tissues, bones and joints, and bloodstream. The new research builds upon a recent discovery by UCSD scientists led by Victor Nizet, MD, professor of pediatrics and pharmacy at UCSD School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences that a key factor in Staph virulence is its ability to survive killing by white blood cells of our immune system. Staph decorates itself with a golden colored pigment that inactivates chemicals designed to rid the body of the pathogen. "We have found that same golden armor used by Staph to thwart our immune system can also be its Achilles' heel", said Nizet.

An important part of the current manuscript was achieved by Wang and colleagues at the Institute of Biological Chemistry at Academia Sinica and the National Taiwan University who used x-ray crystallography to solve the structure of the enzyme that catalyzes the first critical step in Staph golden pigment formation. "The three dimensional structure of the Staph enzyme revealed some striking similarities to squalene synthase, an enzyme involved in human cholesterol production", said Wang, vice-president of Academia Sinica. "In addition, our structural studies pinpointed how these human cholesterol-lowering drug candidates bound to the bacterial enzyme to shut off pigment production.

An original approach for targeting the Staph golden pigment was conceived by Eric Oldfield, PhD, a professor of chemistry and biophysics at the University of Illinois - Urbana-Champaign, who recognized similarities in the golden pigment biosynthesis and the natural pathway for production of human cholesterol. "We predicted that certain chemicals now being explored as potential cholesterol lowering drugs could be redirected at a new target, namely the treatment of difficult Staph infections." Dr. Oldfield's laboratory team then synthesized and analyzed the biochemical properties of many such compounds, revealing a subset that where indeed quite potent at blocking the Staph production of golden pigment. "Although not on the market, some of the best Staph pigment inhibitors have already undergone extensive clinical testing in humans for their effects on cholesterol, so we have evidence these can be safe and well-tolerated medications", said Oldfield.

Preliminary studies to validate the novel Staph treatment strategy were performed in the laboratories of Dr. Nizet at UCSD and George Liu, M.D., Ph.D., assistant professor of pediatrics at Cedar-Sinai Medical Center's Immunobiology Institute in Los Angeles. Exposure to the pigment blocking drug rendered the Staph more susceptible to human white blood cell killing and markedly reduced bacterial levels in a mouse model of severe Staph infection. "This is a entirely new twist on antibacterial therapy", said Liu, "Rather than killing the bacteria directly, the treatment strategy disarms the Staph, thus allowing our own immune system to effectively clear the infection".

The researchers point out several potential advantages of the new Staph pigment inhibition strategy, including less selective pressure for evolution of bacterial drug resistance, fewer side effects on the normal flora, and the ability to work in concert with classical antibiotic approaches. The group hopes partnerships with the biotechnology industry will soon allow the strategy to enter human clinical trials for treatment of complicating infections including those produced by MRSA.

Co-authors contributing to the study were Chia-I Liu, Ph.D. student of Institute of Biochemical Sciences, National Taiwan University and Wen-Yih Jeng, Ph.D. of Academic Sinica, Yongcheng Song, Ph.D. and Fenglin Yin, Ph.D. of the University of Illinois at Urbana-Champaign, and Mary Hensler, Ph.D. of the University of California, San Diego

The research was supported by grants from the National Institutes of Health and the Burroughs-Wellcome Fund in US, and Academia Sinica and National Science Council in Taiwan.

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