A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence
Resource
Science 319 (5868): 1391-1394
Journal
Science
Pages
1391-1394
Date Issued
2008
Date
2008
Author(s)
Liu, Chia-I
Liu, George Y.
Song, Yongcheng
Yin, Fenglin
Hensler, Mary E.
Jeng, Wen-Yih
Nizet, Victor
Wang, Andrew H.-J.
Oldfield, Eric
Abstract
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.
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Other Subjects
bacterial enzyme; bph 651; bph 652; bph 660; bph 661; bph 673; bph 674; bph 698; bph 700; carotenoid; dehydrosqualene synthase; farnesyl thiodiphosphate; squalene synthase; squalene synthase inhibitor; staphyloxanthin; unclassified drug; bacterium; biochemistry; carotenoid; crystal structure; disease treatment; enzyme activity; immune system; inhibitor; metabolism; rodent; sterol; virulence; animal experiment; animal model; article; bacterial virulence; bactericidal activity; blood; cholesterol synthesis; controlled study; crystal structure; drug screening; drug structure; enzyme structure; in vitro study; inhibition kinetics; innate immunity; mouse; nonhuman; priority journal; Staphylococcus aureus; Staphylococcus infection; structure analysis; Amino Acid Sequence; Animals; Anti-Bacterial Agents; Bacterial Proteins; Cell Line; Cell Proliferation; Cholesterol; Crystallography, X-Ray; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Humans; Mice; Molecular Sequence Data; Organothiophosphorus Compounds; Polyisoprenyl Phosphates; Protein Structure, Secondary; Sesquiterpenes; Staphylococcal Infections; Staphylococcus aureus; Virulence; Xanthophylls; Staphylococcus aureus
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