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New approach may render disease-causing staph harmless
Date:2/14/2008

ofessor 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.

The key to the compounds success is that the human and bacterial enzymes it targets are so similar. Andrew Wang and his colleagues at Academia Sinica and the National Taiwan University, both in Taipei, used X-ray crys
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Contact: Diana Yates
diya@uiuc.edu
217-333-5802
University of Illinois at Urbana-Champaign
Source:Eurekalert  

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