A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence.
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 approximately 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.
Liu
Chia-I
CI
Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan.
Liu
George Y
GY
Song
Yongcheng
Y
Yin
Fenglin
F
Hensler
Mary E
ME
Jeng
Wen-Yih
WY
Nizet
Victor
V
Wang
Andrew H-J
AH
Oldfield
Eric
E
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009946:Organothiophosphorus Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011106:Polyisoprenyl Phosphates / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D014774:Virulence / Q000187:drug effects; D024341:Xanthophylls / Q000096:biosynthesis
D000900:Anti-Bacterial Agents; C527434:BPH-652; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D009946:Organothiophosphorus Compounds; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D024341:Xanthophylls; C031841:staphyloxanthin; C004808:farnesyl pyrophosphate; D002784:Cholesterol; C091056:CrtM protein, Staphylococcus aureus; D013186:Farnesyl-Diphosphate Farnesyltransferase