Publication Date:
2008-02-16
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747771/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747771/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Chia-I -- Liu, George Y -- Song, Yongcheng -- Yin, Fenglin -- Hensler, Mary E -- Jeng, Wen-Yih -- Nizet, Victor -- Wang, Andrew H-J -- Oldfield, Eric -- AI07482/AI/NIAID NIH HHS/ -- GM073216/GM/NIGMS NIH HHS/ -- GM65307/GM/NIGMS NIH HHS/ -- HD051796/HD/NICHD NIH HHS/ -- R01 GM065307/GM/NIGMS NIH HHS/ -- R01 GM065307-07/GM/NIGMS NIH HHS/ -- R01 GM073216/GM/NIGMS NIH HHS/ -- R01 GM073216-29/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2008 Mar 7;319(5868):1391-4. doi: 10.1126/science.1153018. Epub 2008 Feb 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18276850" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Animals
;
Anti-Bacterial Agents/chemical synthesis/chemistry/*pharmacology/therapeutic use
;
Bacterial Proteins/*antagonists & inhibitors/chemistry/isolation &
;
purification/metabolism
;
Cell Line
;
Cell Proliferation/drug effects
;
Cholesterol/biosynthesis
;
Crystallography, X-Ray
;
Enzyme Inhibitors/chemical synthesis/metabolism/*pharmacology
;
Farnesyl-Diphosphate Farnesyltransferase/*antagonists &
;
inhibitors/chemistry/isolation & purification/metabolism
;
Humans
;
Mice
;
Molecular Sequence Data
;
Organothiophosphorus Compounds/chemical
;
synthesis/metabolism/*pharmacology/therapeutic use
;
Polyisoprenyl Phosphates/chemistry/metabolism
;
Protein Structure, Secondary
;
Sesquiterpenes/chemistry/metabolism
;
Staphylococcal Infections/*drug therapy/microbiology
;
Staphylococcus aureus/drug effects/growth & development/metabolism/*pathogenicity
;
Virulence/drug effects
;
Xanthophylls/biosynthesis
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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