A drug previously tested as a cholesterol-lowering agent has been successful in blocking staph infection in mice.
This novel approach taken up by an international team of researchers supported by the National Institutes of Health (NIH), may lead to a new direction for therapies against a bacterium that's becoming increasingly resistant to antibiotics.
"By following their scientific instinct about a basic biological process, the researchers made a surprising discovery with important clinical implications. Although the results are still very preliminary, they offer a promising new lead for developing drugs to treat a very timely and medically important health concern," said NIH Director Elias A. Zerhouni, M.D.
The research team was headed by Eric Oldfield, Ph.D., of the University of Illinois at Urbana-Champaign, who had spent decades studying this pathway.
Staphylococcus aureus ("staph") turns golden because of the similar pigment that gives carrots their colour. This pigment acts as an antioxidant in the bacterium to block the reactive oxygen molecules the immune system uses to kill bacteria.
It was thought that the immune system's ability to thwart infection could be restored by blocking pigment formation in staph.
Oldfield read in a magazine on microbial research, how in 2005 University of California, San Diego researchers knocked out a gene in staph's pigment-making pathway to create colourless, and less pathogenic bacteria.
"I looked at the metabolic pathway and noticed that it was similar to the one for the production of cholesterol in humans," said Oldfield.
He wondered that with numerous cholesterol-lowering drugs already on the market and in development, if any could turn staph colorless and make them once again susceptible to the immune system.
His colleagues in Taiwan identified the structure of the enzyme triggering the first critical step in staph's pigment formation and observed striking similarities to an enzyme involved in human cholesterol production. They also captured the structures of several cholesterol-lowering drugs bound to the bacterial enzyme.
Continuing on their 2005 research that sparked the current study, the researchers tested eight different drug compounds that act on the human cholesterol enzyme.
Out of these, 3 blocked pigment production in laboratory tests. When the mice infected with S. aureus were treated with one of the compounds, the bacterial population was reduced by 98 pct.
As the approach reduces the virulence of the bacteria by stopping pigment production, it may not lead to selective pressures on the population, which can lead to antibiotic resistance. It also targets only S. aureus, possibly reducing side effects.
"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.
The results of this study have been described in the recent online edition of Science.