A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence

[Burnham Institute]

http://www.sciencemag.org/cgi/gca?gca=1153018v1&sendit.x=85&sendit.y=7

A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence

Chia-I Liu 1, George Y. Liu 2, Yongcheng Song 3, Fenglin Yin 4, Mary E. Hensler 5, Wen-Yih Jeng 6, Victor Nizet 7*, Andrew H.-J. Wang 1*, Eric Oldfield 8*
1 Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan. ; National Core Facility of High-Throughput Protein Crystallography, Academia Sinica, Nankang, Taipei 11529, Taiwan. ; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 10098, Taiwan.
2 Division of Pediatric Infectious Diseases and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
3 Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
4 Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA.
5 Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
6 Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan. ; National Core Facility of High-Throughput Protein Crystallography, Academia Sinica, Nankang, Taipei 11529, Taiwan.
7 Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
8 Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.; Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA.


Staphylococcus aureus produces hospital and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 ? resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (IC50 ~100 nM), resulting in colorless bacteria with diminished virulence that were cleared in vivo by the innate immune system, providing proof-of-principle for a virulence factor-based therapy against S. aureus.

[sharon sanders]

Re: A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence

Novel Approach Strips Staph of Virulence



An international team of researchers supported by the National Institutes of Health (NIH) has blocked staph infections in mice using a drug previously tested in clinical trials as a cholesterol-lowering agent. The novel approach, described in the February 14 online edition of Science, could offer 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,? said NIH Director Elias A. Zerhouni, M.D. ?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.?
This work was supported by three NIH components: the National Institute of General Medical Sciences, the National Institute of Allergy and Infectious Diseases, and the National Institute of Child Health and Human Development.
A pigment similar to the one that gives carrots their color turns Staphylococcus aureus (?staph?) golden. In the bacterium, this pigment acts as an antioxidant to block the reactive oxygen molecules the immune system uses to kill bacteria.
Researchers had speculated that blocking pigment formation in staph could restore the immune system?s ability to thwart infection. While perusing a magazine on microbial research, Eric Oldfield, Ph.D., of the University of Illinois at Urbana-Champaign read how in 2005 University of California, San Diego researchers knocked out a gene in staph?s pigment-making pathway to create colorless?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, senior author of the Science paper, who had spent decades studying this pathway. With numerous cholesterol-lowering drugs already on the market and in development, he wondered if any could turn staph colorless and make them once again susceptible to the immune system.
Colleagues in Taiwan determined the structure of the enzyme that triggers 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.
Building on their 2005 research that sparked the current study, Victor Nizet, M.D., and George Liu, M.D., Ph.D., now at Cedars-Sinai Medical Center in Los Angeles, Calif., tested eight different drug compounds that act on the human cholesterol enzyme. Three blocked pigment production in laboratory tests. When the researchers treated mice infected with S. aureus with one of the compounds, the bacterial population was reduced by 98 percent.
Because the approach reduces the virulence of the bacteria by stopping pigment production, it may not cause 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.
Contributing authors also include Chia-I Liu, Ph.D., Wen-Yih Jeng, Ph.D., and Andrew H.-J. Wang, Ph.D., of the Academia Sinica in Taipei, Taiwan; Mary E. Hensler, Ph.D., of the University of California, San Diego; and Yongcheng Song, Ph.D., and Fenglin Yin, Ph.D., of the University of Illinois at Urbana-Champaign.

http://www.nigms.nih.gov/News/Results/20080214.htm

[AlaskaDenise]

Re: A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence

.....the bacterial population was reduced by 98 percent.

Because the approach reduces the virulence of the bacteria by stopping pigment production, it may not cause selective pressures on the population, which can lead to antibiotic resistance. It also targets only S. aureus, possibly reducing side effects.

What a amazing discovery.

If the cholesterol drugs can be used as treatement, does it follow that people on these drugs are highly resistant to MRSA?

.