Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Originally published in Science Express on 14 February 2008
Science 7 March 2008:
Vol. 319. no. 5868, pp. 1391 - 1394
DOI: 10.1126/science.1153018
Prev | Table of Contents | Next

Reports

A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence

Chia-I Liu,1,2,3* George Y. Liu,4* Yongcheng Song,5* Fenglin Yin,6 Mary E. Hensler,7 Wen-Yih Jeng,1,2 Victor Nizet,7,8{dagger} Andrew H.-J. Wang,1,2,3{dagger} Eric Oldfield5,6{dagger}

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 angstrom 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 (median inhibitory concentration ~100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor–based therapy against S. aureus.

1 Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan.
2 National Core Facility of High-Throughput Protein Crystallography, Academia Sinica, Nankang, Taipei 11529, Taiwan.
3 Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 10098, Taiwan.
4 Division of Pediatric Infectious Diseases and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
5 Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
6 Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA.
7 Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
8 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: vnizet{at}ucsd.edu (V.N.); ahjwang{at}gate.sinica.edu.tw (A.H.-J.W.); eo{at}chad.scs.uiuc.edu (E.O.)

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Repurposing libraries of eukaryotic protein kinase inhibitors for antibiotic discovery.
C. T. Walsh and M. A. Fischbach (2009)
PNAS 106, 1689-1690
   Full Text »    PDF »
Host-Directed Drug Targeting of Factors Hijacked by Pathogens.
A. Schwegmann and F. Brombacher (2008)
Science Signaling 1, re8
   Abstract »    Full Text »    PDF »
Removing the Golden Coat of Staphylococcus aureus.
R. S. Daum (2008)
N. Engl. J. Med. 359, 85-87
   Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)