快樂小藥師 Im pharmacist nichts glücklich

Submitted on November 15, 2007
Accepted on January 28, 2008

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.

^* To whom correspondence should be addressed.
Victor Nizet , E-mail: vnizet@ucsd.edu
Andrew H.-J. Wang , E-mail: ahjwang@gate.sinica.edu.tw
Eric Oldfield , E-mail: eo@chad.scs.uiuc.edu

These authors contributed equally to this work.

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 Å 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.