title: Two heme-dependent terminal oxidases power Staphylococcus aureus organ-specific colonization of the vertebrate host.
abstract: Staphylococcus aureus is a significant cause of infections worldwide and is able to utilize aerobic respiration, anaerobic respiration, or fermentation as the means by which it generates the energy needed for proliferation. Aerobic respiration is supported by heme-dependent terminal oxidases that catalyze the final step of aerobic respiration, the reduction of O2 to H2O. An inability to respire forces bacteria to generate energy via fermentation, resulting in reduced growth. Elucidating the roles of these energy-generating pathways during colonization of the host could uncover attractive therapeutic targets. Consistent with this idea, we report that inhibiting aerobic respiration by inactivating heme biosynthesis significantly impairs the ability of S. aureus to colonize the host. Two heme-dependent terminal oxidases support aerobic respiration of S. aureus, implying that the staphylococcal respiratory chain is branched. Systemic infection with S. aureus mutants limited to a single terminal oxidase results in an organ-specific colonization defect, resulting in reduced bacterial burdens in either the liver or the heart. Finally, inhibition of aerobic respiration can be achieved by exposing S. aureus to noniron heme analogues. These data provide evidence that aerobic respiration plays a major role in S. aureus colonization of the host and that this energy-generating process is a viable therapeutic target.
  
  
  OBJECTIVE
  Staphylococcus aureus poses a significant threat to public health as antibiotic-resistant isolates of this pathogen continue to emerge. Our understanding of the energy-generating processes that allow S. aureus to proliferate within the host is incomplete. Host-derived heme is the preferred source of nutrient iron during infection; however, S. aureus can synthesize heme de novo and use it to facilitate aerobic respiration. We demonstrate that S. aureus heme biosynthesis powers a branched aerobic respiratory chain composed of two terminal oxidases. The importance of having two terminal oxidases is demonstrated by the finding that each plays an essential role in colonizing distinct organs during systemic infection. Additionally, this process can be targeted by small-molecule heme analogues called noniron protoporphyrins. This study serves to demonstrate that heme biosynthesis supports two terminal oxidases that are required for aerobic respiration and are also essential for S. aureus pathogenesis.
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Hammer
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Reniere
authors.forename: James E
authors.initials: JE
authors.lastname: Cassat
authors.forename: Yaofang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Amanda O
authors.initials: AO
authors.lastname: Hirsch
authors.forename: M
authors.initials: M
authors.lastname: Indriati Hood
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
mesh_terms: D000332:Aerobiosis; D000825:Animal Structures / Q000382:microbiology; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D005260:Female; D000081062:Heme-Binding Proteins; D006420:Hemeproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010088:Oxidoreductases / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D045222:Electron Transport Chain Complex Proteins; D000081062:Heme-Binding Proteins; D006420:Hemeproteins; D037521:Virulence Factors; C404449:heme protein, bacteria; D010088:Oxidoreductases
references.citation: Adv Microb Physiol. 2000;43:165-224
references.pmid: 10907557
references.citation: Science. 2004 Sep 10;305(5690):1626-8
references.pmid: 15361626
references.citation: J Infect Dis. 2006 Jan 15;193(2):172-9
references.pmid: 16362880
references.citation: N Engl J Med. 1998 Aug 20;339(8):520-32
references.pmid: 9709046
references.citation: J Bacteriol. 2010 Jun;192(12):3068-77
references.pmid: 20400547
references.citation: Mol Microbiol. 2012 Dec;86(6):1376-92
references.pmid: 23043465
references.citation: Infect Immun. 2007 Oct;75(10):4891-9
references.pmid: 17698572
references.citation: J Bacteriol. 1990 May;172(5):2250-8
references.pmid: 2110138
references.citation: Appl Environ Microbiol. 2009 Nov;75(21):6910-2
references.pmid: 19717621
references.citation: Mol Microbiol. 1999 Jan;31(2):429-42
references.pmid: 10027961
references.citation: J Bacteriol. 1967 Apr;93(4):1473-4
references.pmid: 5340314
references.citation: J Bacteriol. 1997 Aug;179(15):4706-12
references.pmid: 9244256
references.citation: Science. 2008 Mar 21;319(5870):1672-6
references.pmid: 18356528
references.citation: Microbiology (Reading). 2002 Aug;148(Pt 8):2273-2282
references.pmid: 12177321
references.citation: Arch Biochem Biophys. 1964 May;105:367-79
references.pmid: 14186744
references.citation: Nature. 2010 Sep 23;467(7314):426-9
references.pmid: 20864996
references.citation: Annu Rev Microbiol. 2010;64:357-72
references.pmid: 20528688
references.citation: Res Microbiol. 1999 Oct;150(8):555-66
references.pmid: 10577488
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15629-34
references.pmid: 16227431
references.citation: J Bacteriol. 1999 Feb;181(4):1229-37
references.pmid: 9973350
references.citation: Emerg Infect Dis. 2005 Jun;11(6):868-72
references.pmid: 15963281
references.citation: J Infect Dis. 2003 May 15;187(10):1654-61
references.pmid: 12721946
references.citation: Biochemistry. 1974 Jul 30;13(16):3315-30
references.pmid: 4842277
references.citation: Biochim Biophys Acta. 2011 Nov;1807(11):1398-413
references.pmid: 21756872
references.citation: J Biochem. 1996 Dec;120(6):1055-63
references.pmid: 9010748
references.citation: Nat Rev Microbiol. 2006 Apr;4(4):295-305
references.pmid: 16541137
references.citation: J Bacteriol. 1967 Dec;94(6):1868-74
references.pmid: 4294593
references.citation: Nat Chem Biol. 2009 Feb;5(2):94-6
references.pmid: 19109594
references.citation: Cell. 1992 Jul 24;70(2):267-81
references.pmid: 1638631
references.citation: J Gen Microbiol. 1952 Feb;6(1-2):95-107
references.pmid: 14927856
references.citation: J Bacteriol. 1999 Jan;181(2):501-7
references.pmid: 9882664
references.citation: J Bacteriol. 1969 Nov;100(2):573-8
references.pmid: 5354933
references.citation: Mol Microbiol. 2006 Aug;61(4):927-39
references.pmid: 16859493
references.citation: J Bacteriol. 2006 Jan;188(2):687-93
references.pmid: 16385058
references.citation: Science. 2003 Feb 7;299(5608):906-9
references.pmid: 12574635
references.citation: Proc Natl Acad Sci U S A. 2013 May 14;110(20):8206-11
references.pmid: 23630262
references.citation: J Bacteriol. 2006 Dec;188(23):8079-86
references.pmid: 17108291
references.citation: Infect Immun. 2010 Dec;78(12):4977-89
references.pmid: 20679437
references.citation: Plasmid. 2006 Jan;55(1):58-63
references.pmid: 16051359