February 25, 2008

Cholesterol Drug Makes Staph More Vulnerable

Clusters of round, golden bacteria

An experimental cholesterol-fighting drug can also strip staph bacteria of their golden color and make the microbes more susceptible to killing by the immune system. The finding may lead to new options for battling Staphylococcus aureus bacteria, which are increasingly resistant to antibiotics.

Drug-resistant strains of staph pose a serious public health threat. Recent data from the U.S. Centers for Disease Control and Prevention suggest that these bacteria cause nearly 1 million life-threatening infections each year in the United States. While many researchers have tried to develop new and improved antibiotics—so far with limited success—others have been looking for ways to make the bacteria more vulnerable to immune system attack.

An international research team pieced together a new approach to reduce the virulence of staph by preventing production of its gold-colored pigment. Scientists already knew that the gold pigment helps to protect the bacteria by acting as an antioxidant and deactivating the lethal chemicals released by immune cells. A few years ago, some research team members showed that knocking out a gene in staph's pigment-making pathway could create colorless—and less pathogenic—bacteria. When reading about this finding, Dr. Eric Oldfield of the University of Illinois at Urbana-Champaign made an unexpected observation.

"I looked at the metabolic pathway and noticed that it was similar to the one for the production of cholesterol in humans," Oldfield said.  He is senior author of the new paper, which appeared on February 14, 2008, in the online edition of Science.

Oldfield wondered if it might be possible to block pigment production in staph by using cholesterol-lowering drugs. His team's work was supported in part by 3 NIH components: the National Institute of General Medical Sciences (NIGMS), National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Child Health and Human Development (NICHD).

In collaboration with colleagues in Taiwan, the scientists confirmed that a bacterial enzyme needed to create the gold pigment had a structure that was similar to a human enzyme involved in cholesterol production. Structural studies also showed that several cholesterol-lowering drugs could bind tightly to the bacterial enzyme.

The researchers then tested different drugs that act on the human cholesterol enzyme. They found that the experimental drug BPH-652 was the most effective at preventing pigment production in the bacteria. In a preliminary experiment, the researchers treated staph-infected mice with BPH-652 and found that bacterial levels dropped significantly compared to untreated mice.

Most potential antibiotics aim to directly kill bacteria. These results show that drugs can also be designed to weaken bacterial defenses and make them more vulnerable to the immune system. "This is an entirely new approach that seems to work in animals, and now we need to take the next step to explore if it will work in humans," said Oldfield.

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