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 Andrew H.-J. Wang,^1,2,3 Eric Oldfield^5,6

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.

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.)