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A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence

Chia-I Liu1, George Y Liu, Yongcheng Song

  • 1Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan.

Science (New York, N.Y.)
|February 16, 2008
PubMed

Insights

Researchers found that blocking Staphylococcus aureus

Area of Science:

  • Microbiology
  • Biochemistry
  • Structural Biology

Background:

  • Staphylococcus aureus causes significant infections, with MRSA being a major threat.
  • Staphyloxanthin, a pigment produced by S. aureus, enhances bacterial resistance to host defenses.
  • Enzymatic pathways for staphyloxanthin share similarities with human cholesterol biosynthesis.

Purpose of the Study:

  • To determine the crystal structure of S. aureus dehydrosqualene synthase (CrtM).
  • To investigate the potential of inhibiting staphyloxanthin biosynthesis as a therapeutic strategy against S. aureus.

Main Methods:

  • Determined crystal structures of CrtM at 1.58 angstrom resolution.
  • Screened nine squalene synthase (SQS) inhibitors for activity against CrtM.
  • Determined structures of three SQS inhibitors bound to CrtM.

Main Results:

  • Found structural similarity between CrtM and human SQS.
  • Identified an SQS inhibitor that effectively blocks staphyloxanthin biosynthesis in vitro.
  • Demonstrated that inhibiting staphyloxanthin production increases bacterial susceptibility to host immune clearance in vitro and in vivo.

Conclusions:

  • Targeting staphyloxanthin biosynthesis is a viable strategy against S. aureus infections.
  • Virulence factor-based therapies offer a promising approach to combat antibiotic-resistant bacteria.
  • Structural insights into CrtM can guide the development of novel anti-staphylococcal agents.

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