title: Golden pigment production and virulence gene expression are affected by metabolisms in Staphylococcus aureus.
abstract: The pathogenesis of staphylococcal infections is multifactorial. Golden pigment is an eponymous feature of the human pathogen Staphylococcus aureus that shields the microbe from oxidation-based clearance, an innate host immune response to infection. Here, we screened a collection of S. aureus transposon mutants for pigment production variants. A total of 15 previously unidentified genes were discovered. Notably, disrupting metabolic pathways such as the tricarboxylic acid cycle, purine biosynthesis, and oxidative phosphorylation yields mutants with enhanced pigmentation. The dramatic effect on pigment production seems to correlate with altered expression of virulence determinants. Microarray analysis further indicates that purine biosynthesis impacts the expression of approximately 400 genes involved in a broad spectrum of functions including virulence. The purine biosynthesis mutant and oxidative phosphorylation mutant strains exhibit significantly attenuated virulence in a murine abscess model of infection. Inhibition of purine biosynthesis with a known small-molecule inhibitor results in altered virulence gene expression and virulence attenuation during infection. Taken together, these results suggest an intimate link between metabolic processes and virulence gene expression in S. aureus. This study also establishes the importance of purine biosynthesis and oxidative phosphorylation for in vivo survival.
authors.affiliation: Department of Chemistry, 929 East 57th Street, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Lefu
authors.initials: L
authors.lastname: Lan
authors.forename: Alice
authors.initials: A
authors.lastname: Cheng
authors.forename: Paul M
authors.initials: PM
authors.lastname: Dunman
authors.forename: Dominique
authors.initials: D
authors.lastname: Missiakas
authors.forename: Chuan
authors.initials: C
authors.lastname: He
mesh_terms: D000038:Abscess / Q000382:microbiology; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D053858:Metabolic Networks and Pathways; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010860:Pigments, Biological / Q000378:metabolism*; D040081:Protein Array Analysis; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000235:genetics* / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D010860:Pigments, Biological; D037521:Virulence Factors; C091056:CrtM protein, Staphylococcus aureus; D013186:Farnesyl-Diphosphate Farnesyltransferase
references.citation: FEMS Microbiol Lett. 2003 Sep 12;226(1):121-6
references.pmid: 13129617
references.citation: Nat Chem Biol. 2006 Nov;2(11):591-5
references.pmid: 16980961
references.citation: Microb Pathog. 2009 Aug;47(2):94-100
references.pmid: 19450677
references.citation: Vet Microbiol. 1991 May;27(3-4):371-84
references.pmid: 1882508
references.citation: Mol Microbiol. 1998 Oct;30(2):393-404
references.pmid: 9791183
references.citation: J Med Microbiol. 1991 Mar;34(3):143-7
references.pmid: 2010904
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
references.pmid: 9843981
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13586-91
references.pmid: 18757728
references.citation: Mol Microbiol. 2003 Jun;48(6):1565-78
references.pmid: 12791139
references.citation: J Exp Med. 2009 Oct 26;206(11):2417-27
references.pmid: 19808256
references.citation: Mol Microbiol. 2003 Jun;48(6):1429-49
references.pmid: 12791129
references.citation: J Bacteriol. 1999 Nov;181(21):6585-90
references.pmid: 10542157
references.citation: Infect Immun. 2001 Dec;69(12):7858-65
references.pmid: 11705968
references.citation: J Exp Med. 1956 Jan 1;103(1):109-18
references.pmid: 13278458
references.citation: Microbiol Mol Biol Rev. 2009 Jun;73(2):233-48
references.pmid: 19487727
references.citation: J Bacteriol. 1998 Aug;180(15):3828-36
references.pmid: 9683479
references.citation: J Bacteriol. 2004 Jul;186(13):4085-99
references.pmid: 15205410
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12312-7
references.pmid: 15304642
references.citation: Infect Immun. 2006 Aug;74(8):4655-65
references.pmid: 16861653
references.citation: FEMS Immunol Med Microbiol. 2004 Jan 15;40(1):1-9
references.pmid: 14734180
references.citation: Int J Med Microbiol. 2006 Aug;296(4-5):229-36
references.pmid: 16530010
references.citation: J Biol Chem. 2005 Sep 16;280(37):32493-8
references.pmid: 16020541
references.citation: J Bacteriol. 2001 Feb;183(4):1113-23
references.pmid: 11157922
references.citation: Mol Microbiol. 2009 Jan;71(1):198-211
references.pmid: 19007410
references.citation: N Engl J Med. 1998 Aug 20;339(8):520-32
references.pmid: 9709046
references.citation: Biochem Biophys Res Commun. 2001 Oct 26;288(2):385-9
references.pmid: 11606054
references.citation: Microbiology (Reading). 2004 Feb;150(Pt 2):373-381
references.pmid: 14766915
references.citation: FEMS Microbiol Rev. 2004 May;28(2):183-200
references.pmid: 15109784
references.citation: J Bacteriol. 1994 Dec;176(24):7719-26
references.pmid: 8002598
references.citation: J Bacteriol. 1998 Sep;180(18):4814-20
references.pmid: 9733682
references.citation: J Bacteriol. 2001 Mar;183(6):1843-52
references.pmid: 11222581
references.citation: J Gen Microbiol. 1968 Sep;53(2):147-62
references.pmid: 4976582
references.citation: J Bacteriol. 1997 Oct;179(20):6355-9
references.pmid: 9335283
references.citation: Science. 2008 Mar 7;319(5868):1391-4
references.pmid: 18276850
references.citation: J Bacteriol. 2008 Dec;190(23):7621-32
references.pmid: 18820013
references.citation: J Bacteriol. 2007 Jun;189(11):4275-89
references.pmid: 17384184
references.citation: Infect Immun. 2004 Oct;72(10):6106-11
references.pmid: 15385515
references.citation: Microbes Infect. 2003 Jul;5(9):775-80
references.pmid: 12850203
references.citation: Mol Microbiol. 2007 Sep;65(5):1276-87
references.pmid: 17697253
references.citation: J Bacteriol. 1999 Jan;181(2):501-7
references.pmid: 9882664
references.citation: J Gen Microbiol. 1952 Feb;6(1-2):95-107
references.pmid: 14927856
references.citation: Cell Microbiol. 2008 May;10(5):1058-73
references.pmid: 18067606
references.citation: Microbiology (Reading). 2003 Oct;149(Pt 10):2749-2758
references.pmid: 14523108
references.citation: J Exp Med. 2005 Jul 18;202(2):209-15
references.pmid: 16009720
references.citation: Curr Opin Chem Biol. 2000 Oct;4(5):567-72
references.pmid: 11006546
references.citation: Mol Microbiol. 2006 Aug;61(4):927-39
references.pmid: 16859493
references.citation: Mol Microbiol. 1997 Oct;26(2):399-407
references.pmid: 9383163
references.citation: Infect Immun. 2003 Jan;71(1):516-23
references.pmid: 12496203
references.citation: Plasmid. 2006 Jan;55(1):58-63
references.pmid: 16051359