Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence

• Published in: Science (American Association for the Advancement of Science) Vol. 319; no. 5868; pp. 1391 - 1394
• Main Authors: Liu, Chia -I, Liu, George Y, Song, Yongcheng, Yin, Fenglin, Hensler, Mary E, Jeng, Wen-Yih, Nizet, Victor, Wang, Andrew H.-J, Oldfield, Eric
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 07-03-2008; The American Association for the Advancement of Science
• Subjects: Amino Acid Sequence; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiseptics; Bacteria; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - isolation & purification; Bacterial Proteins - metabolism; Bacteriology; Biochemistry; Biological and medical sciences; Biosynthesis; Carotenoids; Cell Line; Cell Proliferation - drug effects; Cholesterol; Cholesterol - biosynthesis; Cholesterols; Crystallography, X-Ray; Diphosphates; Drug resistance; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzymes; Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors; Farnesyl-Diphosphate Farnesyltransferase - chemistry; Farnesyl-Diphosphate Farnesyltransferase - isolation & purification; Farnesyl-Diphosphate Farnesyltransferase - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Infections; Inhibitor drugs; Ligands; Medical sciences; Mice; Microbiology; Molecular Sequence Data; Organothiophosphorus Compounds - chemical synthesis; Organothiophosphorus Compounds - metabolism; Organothiophosphorus Compounds - pharmacology; Organothiophosphorus Compounds - therapeutic use; Pathogenicity, virulence, toxins, bacteriocins, pyrogens, host-bacteria relations, miscellaneous strains; Pharmacology. Drug treatments; Pigments; Polyisoprenyl Phosphates - chemistry; Polyisoprenyl Phosphates - metabolism; Protein Structure, Secondary; Rodents; Sesquiterpenes - chemistry; Sesquiterpenes - metabolism; Squalene; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - growth & development; Staphylococcus aureus - metabolism; Staphylococcus aureus - pathogenicity; Virulence; Virulence - drug effects; Xanthophylls - biosynthesis; Virulence; Bacteria; Micrococcales; Micrococcaceae; Biosynthesis; Sterol synthesis inhibitor; Cholesterol; Staphylococcus aureus
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1153018

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.