Chapter 5 : Regulation of Virulence by Iron in Gram-Positive Bacteria

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

Regulation of Virulence by Iron in Gram-Positive Bacteria, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555818524/9781555816766_Chap05-1.gif /docserver/preview/fulltext/10.1128/9781555818524/9781555816766_Chap05-2.gif


This chapter discusses the mechanisms by which vertebrates sequester iron from invading pathogens and the response of pathogens to this sequestration. It provides examples of iron-regulated virulence determinants in several clinically important gram-positive bacteria. Iron is crucial to the activity of ribonucleotide reductase, nitrogenase, peroxidase, catalase, and succinic dehydrogenase, and it is therefore required for the vital functions of respiration and several metabolic pathways. During infection, pathogens must rely on their host as the sole source of nutrient iron. Diseases in iron metabolism impact susceptibility to infection, exemplified by an increased frequency of infections caused by , , and in patients with high iron levels. Transcriptional regulation of bacterial genes in response to iron occurs through the activity of metal-dependent regulators. is the causative agent of diphtheria, a contagious upper respiratory tract infection that has been largely eradicated in the last century due to worldwide utilization of the diphtheria vaccines. The iron-containing tetrapyrrole heme is the preferentially bound iron source of . Iron-dependent virulence gene expression in involves a complex regulatory network comprised of Fur and the two-component systems Agr and Sae, which regulate quorum sensing and secreted virulence factors, respectively.

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

Nutritional immunity: host-mediated iron sequestration and theft of iron by pathogens. Vertebrate hosts employ several mechanisms to withhold nutrient iron from invading pathogens during infection. Most iron is located intracellularly, complexed to hemoglobin in erythrocytes or stored within ferritin inside host cells. Lactoferrin (Lf) and transferrin (Tf) transport iron to cells throughout the body and are internalized through the transferrin receptor (Tf R) on host cells. Invading pathogens respond by producing dedicated systems to steal host iron. In some pathogens, hemoglobin is released from erythrocytes following lysis of the cells by bacterial hemolysins and can be imported through the bacterial membrane via heme transporters (HT) or bound by host haptoglobin (Hap) or hemopexin (HP). Host iron can be obtained by the pathogen through direct import via iron transporters (Fe T) or through iron-chelating siderophores (SP), which are secreted from the pathogen to scavenge available extracellular iron. In response, the host produces siderocalin (SC), which can bind some siderophores and prevent them from being utilized by the pathogen. doi:10.1128/9781555818524.ch5f5

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

The Fenton reaction. Ferrous iron catalyzes the reaction, in which hydrogen peroxide is broken down into a hydroxyl radical and hydroxyl anion and the metal is oxidized to ferric iron. Hydroxyl radicals are a form of oxidative stress that damages DNA, proteins, and lipids within a cell. doi:10.1128/9781555818524.ch5f2

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

Mechanism of iron-dependent regulation in gram-positive bacteria. The metalloregulators Fur and DtxR regulate expression of a subset of genes in response to the availability of iron. Under iron-rich conditions, the metal binds to the regulator and activates it, allowing the protein to dimerize and bind to iron boxes in the promoter regions of genes within its regulon. Dimers bind to both strands of the double helix and prevent transcription. When iron levels are low, the regulators are not iron bound and no longer remain bound to the consensus sequence, and transcription is allowed to proceed. doi:10.1128/9781555818524.ch5f3

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4
Figure 4

Structural characteristics of gram-positive metalloregulators. The crystal structures of the two primary iron-dependent metalloregulators in gram-positive bacteria are shown in ribbon diagram ( ). The ferric uptake regulator, Fur, and diphtheria toxin regulator, DtxR, share very little sequence homology but contain similar tertiary structures. The DNA binding domain of both regulators, shown in red, interacts with the consensus iron box sequence in the promoter of Fur- or DtxR-regulated genes. The dimerization domain, shown in blue, allows for two regulator subunits to interact with each other and the DNA strand. The dimerization domain also contains two metal binding sites, shown in green and orange, which bind iron or manganese to activate the regulator and promote DNA binding. DtxR also contains a unique SH3-like domain, shown in yellow, which is attached to the dimerization domain by a flexible linker and is believed to stabilize the molecule while it is bound to DNA. doi:10.1128/9781555818524.ch5f4

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Adilakshmi, T.,, P. D. Ayling,, and C. Ratledge. 2000. Mutational analysis of a role for salicylic acid in iron metabolism of Mycobacterium smegmatis. J. Bacteriol. 182:264271.
2. Allard, M.,, H. Moisan,, E. Brouillette,, A. L. Gervais,, M. Jacques,, P. Lacasse,, M. S. Diarra,, and F. Malouin. 2006. Transcriptional modulation of some Staphylococcus aureus iron-regulated genes during growth in vitro and in a tissue cage model in vivo. Microbes Infect. 8:16791690.
3. Andrade, M. A.,, F. D. Ciccarelli,, C. Perez-Iratxeta,, and P. Bork. 2002. NEAT: a domain duplicated in genes near the components of a putative Fe3+ siderophore transporter from Gram-positive pathogenic bacteria. Genome Biol. 3:RESEARCH0047.
4. Aranda, J.,, M. E. Garrido,, N. Fittipaldi,, P. Cortés,, M. Llagostera,, M. Gottschalk,, and J. Barbé. 2010. The cation-uptake regulators AdcR and Fur are necessary for full virulence of Streptococcus suis. Vet. Microbiol. 144:246249.
5. Arends, J. P.,, and H. C. Zanen. 1988. Meningitis caused by Streptococcus suis in humans. Rev. Infect. Dis. 10:131137.
6. Ashbaugh, C. D.,, and M. R. Wessels. 2001. Absence of a cysteine protease effect on bacterial virulence in two murine models of human invasive group A streptococcal infection. Infect. Immun. 69:66836688.
7. Bacon, J.,, L. G. Dover,, K. A. Hatch,, Y. Zhang,, J. M. Gomes,, S. Kendall,, L. Wernisch,, N. G. Stoker,, P. D. Butcher,, G. S. Besra, et al. 2007. Lipid composition and transcriptional response of Mycobacterium tuberculosis grown under iron-limitation in continuous culture: identification of a novel wax ester. Microbiology 153:14351444.
8. Baichoo, N.,, and J. D. Helmann. 2002. Recognition of DNA by Fur: a reinterpretation of the Fur box consensus sequence. J. Bacteriol. 184:58265832.
9. Baichoo, N.,, T. Wang,, R. Ye,, and J. D. Helmann. 2002. Global analysis of the Bacillus subtilis Fur regulon and the iron starvation stimulon. Mol. Microbiol. 45:16131629.
10. Bates, C.,, G. Montanez,, C. Woods,, R. Vincent,, and Z. Eichenbaum. 2003. Identification and characterization of a Streptococcus pyogenes operon involved in binding of hemoproteins and acquisition of iron. Infect. Immun. 71:10421055.
11. Bates, C. S.,, C. Toukoki,, M. N. Neely,, and Z. Eichenbaum. 2005. Characterization of MtsR, a new metal regulator in group A streptococcus, involved in iron acquisition and virulence. Infect. Immun. 73:57435753.
12. Batey, R. G. 1986. Pathogenesis of caseous lymphadenitis in sheep and goats. Aust. Vet. J. 63:269272.
13. Beasley, F. C.,, C. L. Marolda,, J. Cheung,, S. Buac,, and D. E. Heinrichs. 2011. Staphylococcus aureus transporters Hts, Sir, and Sst capture iron liberated from human transferrin by staphyloferrin A, staphyloferrin B, and catecholamine stress hormones, respectively, and contribute to virulence. Infect. Immun. 79:23452355.
14. Beasley, F. C.,, E. D. Vinés,, J. C. Grigg,, Q. Zheng,, S. Liu,, G. A. Lajoie,, M. E. P. Murphy,, and D. E. Heinrichs. 2009. Characterization of staphyloferrin A biosynthetic and transport mutants in Staphylococcus aureus. Mol. Microbiol. 72:947963.
15. Bierne, H.,, C. Sabet,, N. Personnic,, and P. Cossart. 2007. Internalins: a complex family of leucine-rich repeat-containing proteins in Listeria monocytogenes. Microbes Infect. 9:11561166.
16. Billington, S. J.,, P. A. Esmay,, J. G. Songer,, and B. H. Jost. 2002. Identification and role in virulence of putative iron acquisition genes from Corynebacterium pseudotuberculosis. FEMS Microbiol. Lett. 208:4145.
17. Borezee, E.,, E. Pellegrini,, and P. Berche. 2000. OppA of Listeria monocytogenes, an oligopeptide-binding protein required for bacterial growth at low temperature and involved in intracellular survival. Infect. Immun. 68:70697077.
18. Boyd, J.,, and J. R. Murphy. 1988. Analysis of the diphtheria tox promoter by site-directed mutagenesis. J. Bacteriol. 170:59495952.
19. Braun, V. 1999. Active transport of siderophore-mimicking antibacterials across the outer membrane. Drug Resist. Updates 2:363369.
20. Braun, V.,, A. Pramanik,, T. Gwinner,, M. Köberle,, and E. Bohn. 2009. Sideromycins: tools and antibiotics. BioMetals 22:313.
21. Bray, B.,, I. Sutcliffe,, and D. Harrington. 2009. Expression of the MtsA lipoprotein of Streptococcus agalactiae A909 is regulated by manganese and iron. Antonie van Leeuwenhoek 95:101109.
22. Brenot, A.,, K. Y. King,, and M. G. Caparon. 2005. The PerR regulon in peroxide resistance and virulence of Streptococcus pyogenes. Mol. Microbiol. 55:221234.
23. Brenot, A.,, B. F. Weston,, and M. G. Caparon. 2007. A PerR-regulated metal transporter (PmtA) is an interface between oxidative stress and metal homeostasis in Streptococcus pyogenes. Mol. Microbiol. 63:11851196.
24. Brown, J. S.,, S. M. Gilliland,, and D. W. Holden. 2001. A Streptococcus pneumoniae pathogenicity island encoding an ABC transporter involved in iron uptake and virulence. Mol. Microbiol. 40:572585.
25. Brown, J. S.,, S. M. Gilliland,, J. Ruiz-Albert,, and D. W. Holden. 2002. Characterization of Pit, a Streptococcus pneumoniae iron uptake ABC transporter. Infect. Immun. 70:43894398.
26. Brüggemann, H.,, R. Bauer,, S. Raffestin,, and G. Gottschalk. 2004. Characterization of a heme oxygenase of Clostridium tetani and its possible role in oxygen tolerance. Arch. Microbiol. 182:259263.
27. Bsat, N.,, L. Chen,, and J. Helmann. 1996. Mutation of the Bacillus subtilis alkyl hydroperoxide reductase (ahpCF) operon reveals compensatory interactions among hydrogen peroxide stress genes. J. Bacteriol. 178:65796586.
28. Bsat, N.,, and J. D. Helmann. 1999. Interaction of Bacillus subtilis Fur (ferric uptake repressor) with the dhb operator in vitro and in vivo. J. Bacteriol. 181: 42994307.
29. Cabrera, G.,, A. Xiong,, M. Uebel,, V. K. Singh,, and R. K. Jayaswal. 2001. Molecular characterization of the iron-hydroxamate uptake system in Staphylococcus aureus. Appl. Environ. Microbiol. 67:10011003.
30. Calder, K. M.,, and M. A. Horwitz. 1998. Identification of iron-regulated proteins of Mycobacterium tuberculosis and cloning of tandem genes encoding a low iron-induced protein and a metal transporting ATPase with similarities to two-component metal transport systems. Microb. Pathog. 24:133143.
31. Calderwood, S. B.,, and J. J. Mekalanos. 1988. Confirmation of the Fur operator site by insertion of a synthetic oligonucleotide into an operon fusion plasmid. J. Bacteriol. 170:10151017.
32. Camacho, L. R.,, D. Ensergueix,, E. Perez,, B. Gicquel,, and C. Guilhot. 1999. Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol. Microbiol. 34:257267.
33. Canneva, F.,, M. Branzoni,, G. Riccardi,, R. Provvedi,, and A. Milano. 2005. Rv2358 and FurB: two transcriptional regulators from Mycobacterium tuberculosis which respond to zinc. J. Bacteriol. 187:58375840.
34. Caparon, M. G.,, R. T. Geist,, J. Perez-Casal,, and J. R. Scott. 1992. Environmental regulation of virulence in group A streptococci: transcription of the gene encoding M protein is stimulated by carbon dioxide. J. Bacteriol. 174:56935701.
35. Carlson, P. E., Jr.,, K. A. Carr,, B. K. Janes,, E. C. Anderson,, and P. C. Hanna. 2009. Transcriptional profiling of Bacillus anthracis Sterne (34F2) during iron starvation. PLoS One 4:e6988.
36. Casiano-Colón, A.,, and R. E. Marquis. 1988. Role of the arginine deiminase system in protecting oral bacteria and an enzymatic basis for acid tolerance. Appl. Environ. Microbiol. 54:13181324.
37. Cendrowski, S.,, W. MacArthur,, and P. Hanna. 2004. Bacillus anthracis requires siderophore biosynthesis for growth in macrophages and mouse virulence. Mol. Microbiol. 51:407417.
38. Chavakis, T.,, M. Hussain,, S. M. Kanse,, G. Peters,, R. G. Bretzel,, J.-I. Flock,, M. Herrmann,, and K. T. Preissner. 2002. Staphylococcus aureus extracellular adherence protein serves as anti-inflammatory factor by inhibiting the recruitment of host leukocytes. Nat. Med. 8:687693.
39. Chavakis, T.,, K. Wiechmann,, K. T. Preissner,, and M. Herrmann. 2005. Staphylococcus aureus interactions with the endothelium: the role of bacterial “secretable expanded repertoire adhesive molecules” (SERAM) in disturbing host defense systems. Thromb. Haemost. 94:278285.
40. Chen, L.,, and J. D. Helmann. 1995. Bacillus subtilis MrgA is a Dps(PexB) homologue: evidence for metalloregulation of an oxidative-stress gene. Mol. Microbiol. 18:295300.
41. Chen, L.,, L. P. James,, and J. D. Helmann. 1993. Metalloregulation in Bacillus subtilis: isolation and characterization of two genes differentially repressed by metal ions. J. Bacteriol. 175:54285437.
42. Cheung, J.,, F. C. Beasley,, S. Liu,, G. A. Lajoie,, and D. E. Heinrichs. 2009. Molecular characterization of staphyloferrin B biosynthesis in Staphylococcus aureus. Mol. Microbiol. 74:594608.
43. Chu, G. C.,, K. Katakura,, X. Zhang,, T. Yoshida,, and M. Ikeda-Saito. 1999. Heme degradation as catalyzed by a recombinant bacterial heme oxygenase (Hmu O) from Corynebacterium diphtheriae. J. Biol. Chem. 274:2131921325.
44. Clarke, S. R.,, M. D. Wiltshire,, and S. J. Foster. 2004. IsdA of Staphylococcus aureus is a broad spectrum, iron-regulated adhesin. Mol. Microbiol. 51:15091519.
45. Clemens, D. L.,, and M. A. Horwitz. 1996. The Mycobacterium tuberculosis phagosome interacts with early endosomes and is accessible to exogenously administered transferrin. J. Exp. Med. 184:13491355.
46. Clifton-Hadley, F. A. 1983. Streptococcus suis type 2 infections. Br. Vet. J. 139:15.
47. Cole, S. T.,, R. Brosch,, J. Parkhill,, T. Garnier,, C. Churcher,, D. Harris,, S. V. Gordon,, K. Eiglmeier,, S. Gas,, C. E. Barry, et al. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537544.
48. Conte, M.,, C. Longhi,, M. Polidoro,, G. Petrone,, V. Buonfiglio,, S. Di Santo,, E. Papi,, L. Seganti,, P. Visca,, and P. Valenti. 1996. Iron availability affects entry of Listeria monocytogenes into the enterocytelike cell line Caco-2. Infect. Immun. 64:39253929.
49. Conte, M. P.,, C. Longhi,, G. Petrone,, M. Polidoro,, P. Valenti,, and L. Seganti. 2000. Modulation of actA gene expression in Listeria monocytogenes by iron. J. Med. Microbiol. 49:681683.
50. Cossart, P. 1995. Actin-based bacterial motility. Curr. Opin. Cell Biol. 7:94101.
51. Cotton, J. L.,, J. Tao,, and C. J. Balibar. 2009. Identification and characterization of the Staphylococcus aureus gene cluster coding for staphyloferrin A. Biochemistry 48:10251035.
52. Cowart, R. E.,, and B. G. Foster. 1981. The role of iron in the production of haemolysin by Listeria monocytogenes. Curr. Microbiol. 6:287290.
53. Cox, J. S.,, B. Chen,, M. McNeil,, and W. R. Jacobs. 1999. Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 402:7983.
54. Crosa, J. 1997. Signal transduction and transcriptional and posttranscriptional control of iron-regulated genes in bacteria. Microbiol. Mol. Biol. Rev. 61:319336.
55. Cunningham, M. 2000. Pathogenesis of group A streptococcal infections. Clin. Microbiol. Rev. 13:470511.
56. Dale, S. E.,, A. Doherty-Kirby,, G. Lajoie,, and D. E. Heinrichs. 2004. Role of siderophore biosynthesis in virulence of Staphylococcus aureus: identification and characterization of genes involved in production of a siderophore. Infect. Immun. 72:2937.
57. Dall, L. H.,, and B. L. Herndon. 1990. Association of cell-adherent glycocalyx and endocarditis production by viridans group streptococci. J. Clin. Microbiol. 28:16981700.
58. Davenport, D. S.,, R. M. Massanari,, M. A. Pfaller,, M. J. Bale,, S. A. Streed,, and W. J. Hierholzer. 1986. Usefulness of a test for slime production as a marker for clinically significant infections with coagulase-negative staphylococci. J. Infect. Dis. 153:332339.
59. De Domenico, I.,, D. M. Ward,, C. Langelier,, M. B. Vaughn,, E. Nemeth,, W. I. Sundquist,, T. Ganz,, G. Musci,, and J. Kaplan. 2007. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol. Biol. Cell 18: 25692578.
60. Degnan, B. A.,, M. C. Fontaine,, A. H. Doebereiner,, J. J. Lee,, P. Mastroeni,, G. Dougan,, J. A. Goodacre,, and M. A. Kehoe. 2000. Characterization of an isogenic mutant of Streptococcus pyogenes Manfredo lacking the ability to make streptococcal acid glycoprotein. Infect. Immun. 68:24412448.
61. Deighton, M.,, and R. Borland. 1993. Regulation of slime production in Staphylococcus epidermidis by iron limitation. Infect. Immun. 61:44734479.
62. de Lorenzo, V.,, S. Wee,, M. Herrero,, and J. B. Neilands. 1987. Operator sequences of the aerobactin operon of plasmid ColV-K30 binding the ferric uptake regulation (fur) repressor. J. Bacteriol. 169:26242630.
63. De Voss, J. J.,, K. Rutter,, B. G. Schroeder,, H. Su,, Y. Zhu,, and C. E. Barry. 2000. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc. Natl. Acad. Sci. USA 97:12521257.
64. Dintilhac, A.,, G. Alloing,, C. Granadel,, and J.-P. Claverys. 1997. Competence and virulence of Streptococcus pneumoniae: Adc and PsaA mutants exhibit a requirement for Zn and Mn resulting from inactivation of putative ABC metal permeases. Mol. Microbiol. 25:727739.
65. Drabkin, D. L. 1951. Metabolism of the hemin chromoproteins. Physiol. Rev. 31:345431.
66. Drazek, E. S.,, C. A. Hammack, Sr,, and M. P. Schmitt. 2000. Corynebacterium diphtheriae genes required for acquisition of iron from haemin and haemoglobin are homologous to ABC haemin transporters. Mol. Microbiol. 36:6884.
67. Drechsel, H.,, and G. Jung. 1998. Peptide siderophores. J. Pept. Sci. 4:147181.
68. Dussurget, O.,, M. Rodriguez,, and I. Smith. 1996. An ideR mutant of Mycobacterium smegmatis has derepressed siderophore production and an altered oxidative-stress response. Mol. Microbiol. 22:535544.
69. Dussurget, O.,, J. Timm,, M. Gomez,, B. Gold,, S. Yu,, S. Z. Sabol,, R. K. Holmes, W. R. Jacobs, Jr., and I. Smith. 1999. Transcriptional control of the iron-responsive fxbA gene by the mycobacterial regulator IdeR. J. Bacteriol. 181:34023408.
70. Ellen, R. P.,, D. W. Banting,, and E. D. Fillery. 1985. CLINICAL SCIENCE longitudinal microbiological investigation of a hospitalized population of older adults with a high root surface caries risk. J. Dent. Res. 64:13771381.
71. Ernst, J. F.,, R. L. Bennett,, and L. I. Rothfield. 1978. Constitutive expression of the iron-enterochelin and ferrichrome uptake systems in a mutant strain of Salmonella typhimurium. J. Bacteriol. 135:928934.
72. Escolar, L.,, J. Pérez-Martín,, and V. de Lorenzo. 1999. Opening the iron box: transcriptional metalloregulation by the Fur protein. J. Bacteriol. 181:62236229.
73. Escolar, L.,, J. Pérez-Martín,, and V. de Lorenzo. 1998. Binding of the Fur (ferric uptake regulator) repressor of Escherichia coli to arrays of the GATAAT sequence. J. Mol. Biol. 283:537547.
74. Fabian, M.,, E. Solomaha,, J. S. Olson,, and A. W. Maresso. 2009. Heme transfer to the bacterial cell envelope occurs via a secreted hemophore in the Gram-positive pathogen Bacillus anthracis. J. Biol. Chem. 284:3213832146.
75. Farber, J. M.,, and P. I. Peterkin. 1991. Listeria monocytogenes, a food-borne pathogen. Microbiol. Rev. 55:476511.
76. Fermi, G.,, M. F. Perutz,, B. Shaanan,, and R. Fourme. 1984. The crystal structure of human deoxyhaemoglobin at 1.74 Å resolution. J. Mol. Biol. 175:159174.
77. Ferreras, J. A.,, J.-S. Ryu,, F. Di Lello,, D. S. Tan,, and L. E. N. Quadri. 2005. Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat. Chem. Biol. 1:2932.
78. Fiorini, F.,, S. Stefanini,, P. Valenti,, E. Chiancone,, and D. De Biase. 2008. Transcription of the Listeria monocytogenes fri gene is growth-phase dependent and is repressed directly by Fur, the ferric uptake regulator. Gene 410:113121.
79. Fischetti, V. A. 1989. Streptococcal M protein: molecular design and biological behavior. Clin. Microbiol. Rev. 2:285314.
80. Fischetti, V. A.,, D. A. Parry,, B. L. Trus,, S. K. Hollingshead,, J. R. Scott,, and B. N. Manjula. 1988. Conformational characteristics of the complete sequence of group A streptococcal M6 protein. Proteins 3:6069.
81. Flo, T. H.,, K. D. Smith,, S. Sato,, D. J. Rodriguez,, M. A. Holmes,, R. K. Strong, S. Akira, and A. Aderem. 2004. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432:917921.
82. Fourel, G.,, A. Phalipon,, and M. Kaczorek. 1989. Evidence for direct regulation of diphtheria toxin gene transcription by an Fe2+-dependent DNA-binding repressor, DtoxR, in Corynebacterium diphtheriae. Infect. Immun. 57:32213225.
83. Fuangthong, M.,, A. F. Herbig,, N. Bsat,, and J. D. Helmann. 2002. Regulation of the Bacillus subtilis fur and perR genes by PerR: not all members of the PerR regulon are peroxide inducible. J. Bacteriol. 184:32763286.
84. Gaballa, A.,, H. Antelmann,, C. Aguilar,, S. K. Khakh,, K.-B. Song,, G. T. Smaldone,, and J. D. Helmann. 2008. The Bacillus subtilis iron-sparing response is mediated by a Fur-regulated small RNA and three small, basic proteins. Proc. Natl. Acad. Sci. USA 105:1192711932.
85. Gaballa, A.,, and J. D. Helmann. 1998. Identification of a zinc-specific metalloregulatory protein, Zur, controlling zinc transport operons in Bacillus subtilis. J. Bacteriol. 180:58155821.
86. Gangaidzo, I. T.,, V. M. Moyo,, E. Mvundura,, G. Aggrey,, N. L. Murphree,, H. Khumalo,, T. Saungweme,, I. Kasvosve,, Z. A. R. Gomo,, T. Rouault, et al. 2001. Association of pulmonary tuberculosis with increased dietary iron. J. Infect. Dis. 184:936939.
87. Gat, O.,, G. Zaide,, I. Inbar,, H. Grosfeld,, T. Chitlaru,, H. Levy,, and A. Shafferman. 2008. Characterization of Bacillus anthracis iron-regulated surface determinant (Isd) proteins containing NEAT domains. Mol. Microbiol. 70:983999.
88. Glickman, M. S.,, and W. R. Jacobs. 2001. Microbial pathogenesis of Mycobacterium tuberculosis: dawn of a discipline. Cell 104:477485.
89. Gobin, J.,, and M. A. Horwitz. 1996. Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M. tuberculosis cell wall. J. Exp. Med. 183:15271532.
90. Gold, B.,, G. M. Rodriguez,, S. A. E. Marras,, M. Pentecost,, and I. Smith. 2001. The Mycobacterium tuberculosis IdeR is a dual functional regulator that controls transcription of genes involved in iron acquisition, iron storage and survival in macrophages. Mol. Microbiol. 42:851865.
91. Gomme, P. T.,, K. B. McCann,, and J. Bertolini. 2005. Transferrin: structure, function and potential therapeutic actions. Drug Disc. Today 10:267273.
92. Gupta, R.,, P. Shah,, P., and E. Swiatlo. 2009. Differential gene expression in Streptococcus pneumoniae in response to various iron sources. Microb. Pathog. 47:101109.
93. Haggar, A.,, M. Hussain,, H. Lonnies,, M. Herrmann,, A. Norrby-Teglund,, and J.-I. Flock. 2003. Extracellular adherence protein from Staphylococcus aureus enhances internalization into eukaryotic cells. Infect. Immun. 71:23102317.
94. Hammerschmidt, S.,, G. Bethe,, P. H. Remane,, and G. S. Chhatwal. 1999. Identification of pneumococcal surface protein A as a lactoferrin-binding protein of Streptococcus pneumoniae. Infect. Immun. 67:16831687.
95. Hammond, C. R., 2004. The elements, p. 432. In D. R. Lide (ed.), CRC Handbook of Chemistry and Physics, 85th ed. CRC Press, Boca Raton, FL.
96. Hanks, T.,, M. Liu,, M. McClure,, and B. Lei. 2005. ABC transporter FtsABCD of Streptococcus pyogenes mediates uptake of ferric ferrichrome. BMC Microbiol. 5:62.
97. Hanks, T. S.,, M. Liu,, M. J. McClure,, M. Fukumura,, A. Duffy,, and B. Lei. 2006. Differential regulation of iron- and manganese-specific MtsABC and heme-specific HtsABC transporters by the metalloregulator MtsR of group A streptococcus. Infect. Immun. 74:51325139.
98. Haralalka, S.,, S. Nandi,, and R. K. Bhadra. 2003. Mutation in the relA gene of Vibrio cholerae affects in vitro and in vivo expression of virulence factors. J. Bacteriol. 185:46724682.
99. Hard, G. C. 1972. Examination by electron microscopy of the interaction between peritoneal phagocytes and Corynebacterium ovis. J. Med. Microbiol. 5:483491.
100. Harrison, S. C.,, and A. K. Aggarwal. 1990. DNA recognition by proteins with the helix-turn-helix motif. Annu. Rev. Biochem. 59:933969.
101. Harvie, D. R.,, S. Vílchez,, J. R. Steggles,, and D. J. Ellar. 2005. Bacillus cereus Fur regulates iron metabolism and is required for full virulence. Microbiology 151:569577.
102. Hassan, S.,, K. Ohtani,, R. Wang,, Y. Yuan,, Y. Wang,, Y. Yamaguchi,, and T. Shimizu. 2010. Transcriptional regulation of hemO encoding heme oxygenase in Clostridium perfringens. J. Microbiol. 48:96101.
103. He, Q. Y.,, A. B. Mason,, V. Nguyen,, R. T. MacGillivray,, and R. C. Woodworth. 2000. The chloride effect is related to anion binding in determining the rate of iron release from the human transferrin N-lobe. Biochem J. 350:909915.
104. Heinrichs, J. H.,, L. E. Gatlin,, C. Kunsch,, G. H. Choi,, and M. S. Hanson. 1999. Identification and characterization of SirA, an iron-regulated protein from Staphylococcus aureus. J. Bacteriol. 181:14361443.
105. Henle, E. S.,, and S. Linn. 1997. Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide. J. Biol. Chem. 272:1909519098.
106. Herbig, A. F.,, and J. D. Helmann. 2001. Roles of metal ions and hydrogen peroxide in modulating the interaction of the Bacillus subtilis PerR peroxide regulon repressor with operator DNA. Mol. Microbiol. 41:849859.
107. Herbig, A. F.,, and J. D. Helmann,. 2002. Metal ion uptake and oxidative stress, p. 405414. In A. L. Sonenshein,, J. A. Hoch,, and R. Losick (ed.), Bacillus subtilis and Its Closest Relatives. ASM Press, Washington, DC.
108. Hill, P. J.,, A. Cockayne,, P. Landers,, J. A. Morrissey,, C. M. Sims,, and P. Williams. 1998. SirR, a novel iron-dependent repressor in Staphylococcus epidermidis. Infect. Immun. 66: 41234129.
109. Hoffmaster, A. R.,, J. Ravel,, D. A. Rasko,, G. D. Chapman,, M. D. Chute,, C. K. Marston,, B. K. De,, C. T. Sacchi,, C. Fitzgerald,, L. W. Mayer, et al. 2004. Identification of anthrax toxin genes in a Bacillus cereus associated with an illness resembling inhalation anthrax. Proc. Natl. Acad. Sci. USA 101:84498454.
110. Horsburgh, M. J.,, M. O. Clements,, H. Crossley,, E. Ingham,, and S. J. Foster. 2001a. PerR controls oxidative stress resistance and iron storage proteins and is required for virulence in Staphylococcus aureus. Infect. Immun. 69:37443754.
111. Horsburgh, M. J.,, E. Ingham,, and S. J. Foster. 2001b. In Staphylococcus aureus, Fur is an interactive regulator with PerR, contributes to virulence, and is necessary for oxidative stress resistance through positive regulation of catalase and iron homeostasis. J. Bacteriol. 183:468475.
112. Horsburgh, M. J.,, S. J. Wharton,, A. G. Cox,, E. Ingham,, S. Peacock,, and S. J. Foster. 2002. MntR modulates expression of the PerR regulon and superoxide resistance in Staphylococcus aureus through control of manganese uptake. Mol. Microbiol. 44:12691286.
113. Hussain, M.,, K. Becker,, C. von Eiff,, J. Schrenzel,, G. Peters,, and M. Herrmann. 2001. Identification and characterization of a novel 38.5-kilodalton cell surface protein of Staphylococcus aureus with extended-spectrum binding activity for extracellular matrix and plasma proteins. J. Bacteriol. 183:67786786.
114. Imlay, J. A.,, S. M. Chin,, and S. Linn. 1988. Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science 240:640642.
115. Jain, V.,, R. Saleem-Batcha,, A. China,, and D. Chatterji. 2006. Molecular dissection of the mycobacterial stringent response protein Rel. Protein Sci. 15:14491464.
116. Janulczyk, R.,, J. Pallon,, and L. Bjorck. 1999. Identification and characterization of a Streptococcus pyogenes ABC transporter with multiple specificity for metal cations. Mol. Microbiol. 34:596606.
117. Janulczyk, R.,, S. Ricci,, and L. Bjorck. 2003. MtsABC is important for manganese and iron transport, oxidative stress resistance, and virulence of Streptococcus pyogenes. Infect. Immun. 71:26562664.
118. Jin, B.,, S. M. C. Newton,, Y. Shao,, X. Jiang,, A. Charbit,, and P. E. Klebba. 2006. Iron acquisition systems for ferric hydroxamates, haemin and haemoglobin in Listeria monocytogenes. Mol. Microbiol. 59:11851198.
119. Johnson, M.,, A. Cockayne,, P. H. Williams,, and J. A. Morrissey. 2005. Iron-responsive regulation of biofilm formation in Staphylococcus aureus involves Fur-dependent and Fur-independent mechanisms. J. Bacteriol. 187:82118215.
120. Johnson, M.,, M. Sengupta,, J. Purves,, E. Tarrant,, P. H. Williams,, A. Cockayne,, A. Muthaiyan,, R. Stephenson,, N. Ledala,, B. J. Wilkinson, et al. 2011. Fur is required for the activation of virulence gene expression through the induction of the sae regulatory system in Staphylococcus aureus. Int. J. Med. Microbiol. 301:4452.
121. Johri, A. K.,, L. C. Paoletti,, P. Glaser,, M. Dua,, P. K. Sharma,, G. Grandi,, and R. Rappuoli. 2006. Group B streptococcus: global incidence and vaccine development. Nat. Rev. Microbiol. 4:932942.
122. Kansal, R. G.,, R. K. Aziz,, and M. Kotb. 2005. Modulation of expression of superantigens by human transferrin and lactoferrin: a novel mechanism in host-streptococcus interactions. J. Infect. Dis. 191:21212129.
123. Kazmi, S. U.,, R. Kansal,, R. K. Aziz,, M. Hooshdaran,, A. Norrby-Teglund,, D. E. Low,, A.-B. Halim,, and M. Kotb. 2001. Reciprocal, temporal expression of SpeA and SpeB by invasive M1T1 group A streptococcal isolates in vivo. Infect. Immun. 69:49884995.
124. Kitten, T.,, C. L. Munro,, S. M. Michalek,, and F. L. Macrina. 2000. Genetic characterization of a Streptococcus mutans LraI family operon and role in virulence. Infect. Immun. 68:44414451.
125. Kotb, M. 1995. Bacterial pyrogenic exotoxins as superantigens. Clin. Microbiol. Rev. 8:411426.
126. Kotiranta, A.,, K. Lounatmaa,, and M. Haapasalo. 2000. Epidemiology and pathogenesis of Bacillus cereus infections. Microbes Infect. 2:189198.
127. Kramer, J. M.,, and R. J. Gilbert,. 1989. Bacillus cereus and other Bacillus species, p. 2170. In M. P. Doyle (ed.), Foodborne Bacterial Pathogens. Marcel Dekker, New York, NY.
128. Kristiansen, M.,, J. H. Graversen,, C. Jacobsen,, O. Sonne,, H.-J. Hoffman,, S. K. A. Law,, and S. K. Moestrup. 2001. Identification of the haemoglobin scavenger receptor. Nature 409:198201.
129. Kunkle, C. A.,, and M. P. Schmitt. 2003. Analysis of the Corynebacterium diphtheriae DtxR regulon: identification of a putative siderophore synthesis and transport system that is similar to the Yersinia high-pathogenicity island-encoded yersiniabactin synthesis and uptake system. J. Bacteriol. 185:68266840.
130. Lancefield, R. C. 1962. Current knowledge of type-specific M antigens of group A streptococci. J. Immunol. 89:307313.
131. Lee, J.-W.,, and J. D. Helmann. 2006. The PerR transcription factor senses H2O2 by metal-catalysed histidine oxidation. Nature 440:363367.
132. Lereclus, D.,, H. Agaisse,, C. Grandvalet,, S. Salamitou,, and M. Gominet. 2000. Regulation of toxin and virulence gene transcription in Bacillus thuringiensis. Int. J. Med. Microbiol. 290:295299.
133. Li, W.,, L. Liu,, H. Chen,, and R. Zhou. 2009. Identification of Streptococcus suis genes preferentially expressed under iron starvation by selective capture of transcribed sequences. FEMS Microbiol. Lett. 292:123133.
134. Lim, W. S.,, J. T. Macfarlane,, T. C. J. Boswell,, T. G. Harrison,, D. Rose,, M. Leinonen,, and P. Saikku. 2001. Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines. Thorax 56:296301.
135. Lincoln, R. E.,, D. R. Hodges,, F. Klein,, B. G. Mahlandt,, W. I. Jones,, B. W. Haines,, M. A. Rhian,, and J. S. Walker. 1965. Role of the lymphatics in the pathogenesis of anthrax. J. Infect. Dis. 115:481494.
136. Lindsay, J. A.,, and S. J. Foster. 2001. zur: a Zn2+-responsive regulatory element of Staphylococcus aureus. Microbiology 147:12591266.
137. Litwin, C. M.,, S. A. Boyko,, and S. B. Calderwood. 1992. Cloning, sequencing, and transcriptional regulation of the Vibrio cholerae fur gene. J. Bacteriol. 174:18971903.
138. Litwin, C. M.,, and S. B. Calderwood. 1993. Role of iron in regulation of virulence genes. Clin. Microbiol. Rev. 6:137149.
139. Lucarelli, D.,, M. L. Vasil,, W. Meyer-Klaucke,, and E. Pohl. 2008. The metal-dependent regulators FurA and FurB from Mycobacterium tuberculosis. Int. J. Mol. Sci. 9:15481560.
140. Luo, Y.,, Z. Han,, S. M. Chin,, and S. Linn. 1994. Three chemically distinct types of oxidants formed by iron-mediated Fenton reactions in the presence of DNA. Proc. Natl. Acad. Sci. USA 91:1243812442.
141. Magnus, S. A.,, I. R. Hambleton,, F. Moosdeen,, and G. R. Serjeant. 1999. Recurrent infections in homozygous sickle cell disease. Arch. Dis. Child. 80:537541.
142. Manabe, Y. C.,, B. J. Saviola,, L. Sun,, J. R. Murphy,, and W. R. Bishai. 1999. Attenuation of virulence in Mycobacterium tuberculosis expressing a constitutively active iron repressor. Proc. Natl. Acad. Sci. USA 96:1284412848.
143. Maresso, A. W.,, G. Garufi,, and O. Schneewind. 2008. Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin. PLoS Pathog. 4:e1000132.
144. Marra, A.,, J. Asundi,, M. Bartilson,, S. Lawson,, F. Fang,, J. Christine,, C. Wiesner,, D. Brigham,, W. P. Schneider,, and A. E. Hromockyj. 2002. Differential fluorescence induction analysis of Streptococcus pneumoniae identifies genes involved in pathogenesis. Infect. Immun. 70:14221433.
145. Maskell, J. P. 1980. The functional interchangeability of enterobacterial and staphylococcal iron chelators. Antonie van Leeuwenhoek 46:343351.
146. McIver, K.,, A. Heath,, and J. Scott. 1995. Regulation of virulence by environmental signals in group A streptococci: influence of osmolarity, temperature, gas exchange, and iron limitation on emm transcription. Infect. Immun. 63:45404542.
147. McNamara, P. J.,, G. A. Bradley,, and J. G. Songer. 1994. Targeted mutagenesis of the phospholipase D gene results in decreased virulence of Corynebacterium pseudotuberculosis. Mol. Microbiol. 12:921930.
148. Miller, M. J.,, and F. Malouin. 1993. Microbial iron chelators as drug delivery agents: the rational design and synthesis of siderophore-drug conjugates. Accounts Chem. Res. 26:241249.
149. Minnikin, D. E.,, L. Kremer,, L. G. Dover,, and G. S. Besra. 2002. The methyl-branched fortifications of Mycobacterium tuberculosis. Chem. Biol. 9:545553.
150. Moelling, C.,, R. Oberschlacke,, P. Ward,, J. Karijolich,, K. Borisova,, N. Bjelos,, and L. Bergeron. 2007. Metal-dependent repression of siderophore and biofilm formation in Actinomyces naeslundii. FEMS Microbiol. Lett. 275:214220.
151. Montanez, G. E.,, M. N. Neely,, and Z. Eichenbaum. 2005. The streptococcal iron uptake (Siu) transporter is required for iron uptake and virulence in a zebrafish infection model. Microbiology 151:37493757.
152. Moreira, L. D. O.,, A. F. B. Andrade,, M. D. Vale,, S. M. S. Souza,, R. Hirata, Jr.,, L. M. O. B. Asad,, N. R. Asad,, L. H. Monteiro-Leal,, J. O. Previato,, and A. L. Mattos-Guaraldi. 2003. Effects of iron limitation on adherence and cell surface carbohydrates of Corynebacterium diphtheriae strains. Appl. Environ. Microbiol. 69:59075913.
153. Morgan, J. W.,, and E. Anders. 1980. Chemical composition of Earth, Venus, and Mercury. Proc. Natl. Acad. Sci. USA 77:69736977.
154. Morrissey, J. A.,, A. Cockayne,, P. J. Hill,, and P. Williams. 2000. Molecular cloning and analysis of a putative siderophore ABC transporter from Staphylococcus aureus. Infect. Immun. 68:62816288.
155. Moyo, V. M.,, I. T. Gangaidzo,, V. R. Gordeuk,, C. F. Kiire,, and A. P. Macphail. 1997. Tuberculosis and iron overload in Africa: a review. Cent. Afr. J. Med. 43:334339.
156. Murray, M. J.,, A. B. Murray,, M. B. Murray,, and C. J. Murray. 1978. The adverse effect of iron repletion on the course of certain infections. Br. Med. J. 2:11131115.
157. Nelson, A. L.,, J. M. Barasch,, R. M. Bunte,, and J. N. Weiser. 2005. Bacterial colonization of nasal mucosa induces expression of siderocalin, an iron-sequestering component of innate immunity. Cell. Microbiol. 7:14041417.
158. Newton, S. M. C.,, P. E. Klebba,, C. Raynaud,, Y. Shao,, X. Jiang,, I. Dubail,, C. Archer,, C. Frehel,, and A. Charbit. 2005. The svpA-srtB locus of Listeria monocytogenes: Fur-mediated iron regulation and effect on virulence. Mol. Microbiol. 55:927940.
159. Nikaido, H.,, and J. A. Hall. 1998. Overview of bacterial ABC transporters. Methods Enzymol. 292:320.
160. Olsen, K. N.,, M. H. Larsen,, C. G. M. Gahan,, B. Kallipolitis,, X. A. Wolf,, R. Rea,, C. Hill,, and H. Ingmer. 2005. The Dps-like protein Fri of Listeria monocytogenes promotes stress tolerance and intracellular multiplication in macrophage-like cells. Microbiology 151:925933.
161. Oram, D. M.,, A. Avdalovic,, and R. K. Holmes. 2002. Construction and characterization of transposon insertion mutations in Corynebacterium diphtheriae that affect expression of the diphtheria toxin repressor (DtxR). J. Bacteriol. 184:57235732.
162. Osaki, M.,, D. Takamatsu,, Y. Shimoji,, and T. Sekizaki. 2002. Characterization of Streptococcus suis genes encoding proteins homologous to sortase of gram-positive bacteria. J. Bacteriol. 184:971982.
163. Palma, M.,, A. Haggar,, and J. I. Flock. 1999. Adherence of Staphylococcus aureus is enhanced by an endogenous secreted protein with broad binding activity. J. Bacteriol. 181:28402845.
164. Peters, G.,, R. Locci,, and G. Pulverer. 1982. Adherence and growth of coagulase-negative staphylococci on surfaces of intravenous catheters. J. Infect. Dis. 146:479482.
165. Pfleger, B. F.,, Y. Kim,, T. D. Nusca,, N. Maltseva,, J. Y. Lee,, C. M. Rath,, J. B. Scaglione,, B. K. Janes,, E. C. Anderson,, N. H. Bergman, et al. 2008. Structural and functional analysis of AsbF: origin of the stealth 3,4-dihydroxybenzoic acid subunit for petrobactin biosynthesis. Proc. Natl. Acad. Sci. USA 105:1713317138.
166. Pohl, E.,, J. C. Haller,, A. Mijovilovich,, W. Meyer-Klaucke,, E. Garman,, and M. L. Vasil. 2003. Architecture of a protein central to iron homeostasis: crystal structure and spectroscopic analysis of the ferric uptake regulator. Mol. Microbiol. 47:903915.
167. Pohl, E.,, R. K. Holmes,, and W. G. Hol. 1998. Motion of the DNA-binding domain with respect to the core of the diphtheria toxin repressor (DtxR) revealed in the crystal structure of apo- and holo-DtxR. J. Biol. Chem. 273:2242022427.
168. Polidoro, M.,, D. De Biase,, B. Montagnini,, L. Guarrera,, S. Cavallo,, P. Valenti,, S. Stefanini,, and E. Chiancone. 2002. The expression of the dodecameric ferritin in Listeria spp. is induced by iron limitation and stationary growth phase. Gene 296:121128.
169. Posey, J. E.,, and F. C. Gherardini. 2000. Lack of a role for iron in the Lyme disease pathogen. Science 288:16511653.
170. Poulos, T. L. 2007. The Janus nature of heme. Nat. Prod. Rep. 24:504510.
171. Primm, T. P.,, S. J. Andersen,, V. Mizrahi,, D. Avarbock,, H. Rubin,, and C. E. Barry III. 2000. The stringent response of Mycobacterium tuberculosis is required for long-term survival. J. Bacteriol. 182:48894898.
172. Pym, A. S.,, P. Domenech,, N. Honoré,, J. Song,, V. Deretic,, and S. T. Cole. 2001. Regulation of catalase-peroxidase (KatG) expression, isoniazid sensitivity and virulence by furA of Mycobacterium tuberculosis. Mol. Microbiol. 40:879889.
173. Qian, Y.,, J. H. Lee,, and R. K. Holmes. 2002. Identification of a DtxR-regulated operon that is essential for siderophore-dependent iron uptake in Corynebacterium diphtheriae. J. Bacteriol. 184:48464856.
174. Que, Q.,, and J. D. Helmann. 2000. Manganese homeostasis in Bacillus subtilis is regulated by MntR, a bifunctional regulator related to the diphtheria toxin repressor family of proteins. Mol. Microbiol. 35:14541468.
175. Rachman, H.,, M. Strong,, U. Schaible,, J. Schuchhardt,, K. Hagens,, H. Mollenkopf,, D. Eisenberg,, and S. H. E. Kaufmann. 2006. Mycobacterium tuberculosis gene expression profiling within the context of protein networks. Microbes Infect. 8:747757.
176. Ratledge, C., 1999. Iron metabolism, p. 260286. In C. Ratledge, and J. Dale (ed.), Mycobacteria: Molecular Biology and Virulence. Blackwell Science, London, United Kingdom.
177. Ratledge, C.,, and F. G. Winder. 1962. The accumulation of salicylic acid by mycobacteria during growth on an iron-deficient medium. Biochem. J. 84:501506.
178. Rea, R. B.,, C. G. M. Gahan,, and C. Hill. 2004. Disruption of putative regulatory loci in Listeria monocytogenes demonstrates a significant role for Fur and PerR in virulence. Infect. Immun. 72:717727.
179. Read, T. D.,, S. N. Peterson,, N. Tourasse,, L. W. Baillie,, I. T. Paulsen,, K. E. Nelson,, H. Tettelin,, D. E. Fouts,, J. A. Eisen,, S. R. Gill, et al. 2003. The genome sequence of Bacillus anthracis Ames and comparison to closely related bacteria. Nature 423:8186.
180. Reed, M. B.,, P. Domenech,, C. Manca,, H. Su,, A. K. Barczak,, B. N. Kreiswirth,, G. Kaplan,, and C. E. Barry. 2004. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431:8487.
181. Ricci, S.,, R. Janulczyk,, and L. Bjorck. 2002. The regulator PerR is involved in oxidative stress response and iron homeostasis and is necessary for full virulence of Streptococcus pyogenes. Infect. Immun. 70:49684976.
182. Rodriguez, G. M. 2006. Control of iron metabolism in Mycobacterium tuberculosis. Trends Microbiol. 14:320327.
183. Rodriguez, G. M.,, B. Gold,, M. Gomez,, O. Dussurget,, and I. Smith. 1999. Identification and characterization of two divergently transcribed iron regulated genes in Mycobacterium tuberculosis. Tuber. Lung Dis. 79:287298.
184. Rodriguez, G. M.,, and I. Smith. 2003. Mechanisms of iron regulation in mycobacteria: role in physiology and virulence. Mol. Microbiol. 47:14851494.
185. Rodriguez, G. M.,, and I. Smith. 2006. Identification of an ABC transporter required for iron acquisition and virulence in Mycobacterium tuberculosis. J. Bacteriol. 188:424430.
186. Rodriguez, G. M.,, M. I. Voskuil,, B. Gold,, G. K. Schoolnik,, and I. Smith. 2002. ideR, an essential gene in Mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infect. Immun. 70:33713381.
187. Rolerson, E.,, A. Swick,, L. Newlon,, C. Palmer,, Y. Pan,, B. Keeshan,, and G. Spatafora. 2006. The SloR/Dlg metalloregulator modulates Streptococcus mutans virulence gene expression. J. Bacteriol. 188:50335044.
188. Roosenberg, J. M. N.,, Y. M. Lin,, Y. Lu,, and M. J. Miller. 2000. Studies and syntheses of siderophores, microbial iron chelators, and analogs as potential drug delivery agents. Curr. Med. Chem. 7:159197.
189. Russell, L. M.,, S. J. Cryz, Jr.,, and R. K. Holmes. 1984. Genetic and biochemical evidence for a siderophore-dependent iron transport system in Corynebacterium diphtheriae. Infect. Immun. 45:143149.
190. Sala, C.,, F. Forti,, E. Di Florio,, F. Canneva,, A. Milano,, G. Riccardi,, and D. Ghisotti. 2003. Mycobacterium tuberculosis FurA autoregulates its own expression. J. Bacteriol. 185:53575362.
191. Schaible, U. E.,, H. L. Collins,, F. Priem,, and S. H. E. Kaufmann. 2002. Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J. Exp. Med. 196:15071513.
192. Schiering, N.,, X. Tao,, H. Zeng,, J. R. Murphy,, G. A. Petsko,, and D. Ringe. 1995. Structures of the apo- and the metal ion-activated forms of the diphtheria tox repressor from Corynebacterium diphtheriae. Proc. Natl. Acad. Sci. USA 92:98439850.
193. Schmitt, M. 1997. Transcription of the Corynebacterium diphtheriae hmuO gene is regulated by iron and heme. Infect. Immun. 65:46344641.
194. Schmitt, M. P. 1999. Identification of a two-component signal transduction system from Corynebacterium diphtheriae that activates gene expression in response to the presence of heme and hemoglobin. J. Bacteriol. 181:53305340.
195. Schmitt, M. P.,, and R. K. Holmes. 1993. Analysis of diphtheria toxin repressor-operator interactions and characterization of a mutant repressor with decreased binding activity for divalent metals. Mol. Microbiol. 9:173181.
196. Schneider, R.,, and K. Hantke. 1993. Iron-hydroxamate uptake systems in Bacillus subtilis: identification of a lipoprotein as part of a binding protein-dependent transport system. Mol. Microbiol. 8:111121.
197. Schüpbach, P.,, V. Osterwalder,, and B. Guggenheim. 1995. Human root caries: microbiota in plaque covering sound, carious and arrested carious root surfaces. Caries Res. 29:382395.
198. Sebulsky, M. T.,, and D. E. Heinrichs. 2001. Identification and characterization of fhuD1 and fhuD2, two genes involved in iron-hydroxamate uptake in Staphylococcus aureus. J. Bacteriol. 183:49945000.
199. Sebulsky, M. T.,, D. Hohnstein,, M. D. Hunter,, and D. E. Heinrichs. 2000. Identification and characterization of a membrane permease involved in iron-hydroxamate transport in Staphylococcus aureus. J. Bacteriol. 182: 43944400.
200. Siegrist, M. S.,, M. Unnikrishnan,, M. J. McConnell,, M. Borowsky,, T. Y. Cheng,, N. Siddiqi,, S. M. Fortune,, D. B. Moody,, and E. J. Rubin. 2009. Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition. Proc. Natl. Acad. Sci. USA 106:1879218797.
201. Simon, N.,, V. Coulanges,, P. Andre,, and D. J. Vidon. 1995. Utilization of exogenous siderophores and natural catechols by Listeria monocytogenes. Appl. Environ. Microbiol. 61:16431645.
202. Skaar, E. P.,, A. H. Gaspar,, and O. Schneewind. 2004b. IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus. J. Biol. Chem. 279:436443.
203. Skaar, E. P.,, A. H. Gaspar,, and O. Schneewind. 2006. Bacillus anthracis IsdG, a heme-degrading monooxygenase. J. Bacteriol. 188:10711080.
204. Skaar, E. P.,, M. Humayun,, T. Bae,, K. L. DeBord,, and O. Schneewind. 2004a. Iron-source preference of Staphylococcus aureus infections. Science 305:16261628.
205. Skaar, E. P.,, and O. Schneewind. 2004. Iron-regulated surface determinants (Isd) of Staphylococcus aureus: stealing iron from heme. Microbes Infect. 6:390397.
206. Smith, G. A.,, and D. A. Portnoy. 1997. How the Listeria monocytogenes ActA protein converts actin polymerization into a motile force. Trends Microbiol. 5:272276.
207. Smith, H.,, J. Keppie,, and J. L. Stanley. 1954. Observations on the cause of death in experimental anthrax. Lancet 267:474476.
208. Sow, F. B.,, W. C. Florence,, A. R. Satoskar,, L. S. Schlesinger,, B. S. Zwilling,, and W. P. Lafuse. 2007. Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J. Leukoc. Biol. 82:934945.
209. Speziali, C. D.,, S. E. Dale,, J. A. Henderson,, E. D. Vines,, and D. E. Heinrichs. 2006. Requirement of Staphylococcus aureus ATP-binding cassette-ATPase FhuC for iron-restricted growth and evidence that it functions with more than one iron transporter. J. Bacteriol. 188:20482055.
210. Stojiljkovic, I.,, and K. Hantke. 1995. Functional domains of the Escherichia coli ferric uptake regulator protein (Fur). Mol. Gen. Genet. 247:199205.
211. Sturgill-Koszycki, S.,, U. E. Schaible,, and D. G. Russell. 1996. Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis. EMBO J. 15:69606968.
212. Tai, S.-P. S.,, A. E. Krafft,, P. Nootheti,, and R. K. Holmes. 1990. Coordinate regulation of siderophore and diphtheria toxin production by iron in Corynebacterium diphtheriae. Microb. Pathog. 9:267273.
213. Tai, S. S.,, C. J. Lee,, and R. E. Winter. 1993. Hemin utilization is related to virulence of Streptococcus pneumoniae. Infect. Immun. 61:54015405.
214. Tao, X.,, J. Boyd,, and J. R. Murphy. 1992. Specific binding of the diphtheria tox regulatory element DtxR to the tox operator requires divalent heavy metal ions and a 9-base-pair interrupted palindromic sequence. Proc. Natl. Acad. Sci. USA 89:58975901.
215. Tarlovsky, Y.,, M. Fabian,, E. Solomaha,, E. Honsa,, J. S. Olson,, and A. W. Maresso. 2010. A Bacillus anthracis S-layer homology protein that binds heme and mediates heme delivery to IsdC. J. Bacteriol. 192:35033511.
216. Tashjian, J. J.,, and S. G. Campbell. 1983. Interaction between caprine macrophages and Corynebacterium pseudotuberculosis: an electron microscopic study. Am. J. Vet. Res. 44:690693.
217. Taylor, C. M.,, M. Beresford,, H. A. S. Epton,, D. C. Sigee,, G. Shama,, P. W. Andrew,, and I. S. Roberts. 2002. Listeria monocytogenes relA and hpt mutants are impaired in surface-attached growth and virulence. J. Bacteriol. 184:621628.
218. Tettelin, H.,, K. E. Nelson,, I. T. Paulsen,, J. A. Eisen,, T. D. Read,, S. Peterson,, J. Heidelberg,, R. T. DeBoy,, D. H. Haft,, R. J. Dodson, et al. 2001. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science 293:498506.
219. Throup, J. P.,, K. K. Koretke,, A. P. Bryant,, K. A. Ingraham,, A. F. Chalker,, Y. Ge,, A. Marra,, N. G. Wallis,, J. R. Brown,, D. J. Holmes, et al. 2000. A genomic analysis of two-component signal transduction in Streptococcus pneumoniae. Mol. Microbiol. 35:566576.
220. Tilney, L. G.,, and D. A. Portnoy. 1989. Actin filaments and the growth, movement, and spread of the intracellular bacterial parasite, Listeria monocytogenes. J. Cell Biol. 109:15971608.
221. Timmins, G. S.,, and V. Deretic. 2006. Mechanisms of action of isoniazid. Mol. Microbiol. 62:12201227.
222. Tolosano, E.,, and F. Altruda. 2002. Hemopexin: structure, function, and regulation. DNA Cell Biol. 21:297306.
223. Torres, V. J.,, A. S. Attia,, W. J. Mason,, M. I. Hood,, B. D. Corbin,, F. C. Beasley,, K. L. Anderson,, D. L. Stauff,, W. H. McDonald,, L. J. Zimmerman, et al. 2010. Staphylococcus aureus Fur regulates the expression of virulence factors that contribute to the pathogenesis of pneumonia. Infect. Immun. 78:16181628.
224. Torres, V. J.,, G. Pishchany,, M. Humayun,, O. Schneewind,, and E. P. Skaar. 2006. Staphylococcus aureus IsdB is a hemoglobin receptor required for heme iron utilization. J. Bacteriol. 188:84218429.
225. Toukoki, C.,, K. M. Gold,, K. S. McIver,, and Z. Eichenbaum. 2010. MtsR is a dual regulator that controls virulence genes and metabolic functions in addition to metal homeostasis in the group A streptococcus. Mol. Microbiol. 76:971989.
226. Uchida, T.,, D. M. Gill,, and A. M. Pappenheimer, Jr. 1971. Mutation in the structural gene for diphtheria toxin carried by temperate phage. Nat. New Biol. 233: 811.
227. Ulijasz, A. T.,, D. R. Andes,, J. D. Glasner,, and B. Weisblum. 2004. Regulation of iron transport in Streptococcus pneumoniae by RitR, an orphan response regulator. J. Bacteriol. 186:81238136.
228. Vértesy, L.,, W. Aretz,, H.-W. Fehlhaber,, and H. Kogler. 1995. Salmycin A-D, Antibiotika aus Streptomyces violaceus, DSM 8286, mit Siderophor-Aminoglycosid-Struktur. Helv. Chim. Acta 78: 4660.
229. von Eiff, C.,, R. A. Proctor,, and G. Peters. 2001. Coagulase-negative staphylococci. Pathogens have major role in nosocomial infections. Postgrad. Med. 110:6364, 6970, 7376.
230. Voyich, J. M.,, K. R. Braughton,, D. E. Sturdevant,, A. R. Whitney,, B. Saïd-Salim,, S. F. Porcella,, R. D. Long,, D. W. Dorward,, D. J. Gardner,, B. N. Kreiswirth, et al. 2005. Insights into mechanisms used by Staphylococcus aureus to avoid destruction by human neutrophils. J. Immunol. 175:39073919.
231. Voyich, J. M.,, C. Vuong,, M. DeWald,, T. K. Nygaard,, S. Kocianova,, S. Griffith,, J. Jones,, C. Iverson,, D. E. Sturdevant,, K. R. Braughton, et al. 2009. The SaeR/S gene regulatory system is essential for innate immune evasion by Staphylococcus aureus. J. Infect. Dis. 199:16981706.
232. Wandersman, C.,, and P. Delepelaire. 2004. Bacterial iron sources: from siderophores to hemophores. Annu. Rev. Microbiol. 58:611647.
233. Wang, L.,, and B. J. Cherayil. 2009. Ironing out the wrinkles in host defense: interactions between iron homeostasis and innate immunity. J. Innate Immun. 1:455464.
234. Wang, Z.,, C. Li,, M. Ellenburg,, E. Soistman,, J. Ruble,, B. Wright,, J. X. Ho,, and D. C. Carter. 2006. Structure of human ferritin L chain. Acta Crystallogr. D 62:800806.
235. Weems, J. J., Jr. 2001. The many faces of Staphylococcus aureus infection. Recognizing and managing its life-threatening manifestations. Postgrad. Med. 110, 2426, 2931, 3536.
236. Welcher, B. C.,, J. H. Carra,, L. DaSilva,, J. Hanson,, C. S. David,, M. J. Aman,, and S. Bavari. 2002. Lethal shock induced by streptococcal pyrogenic exotoxin A in mice transgenic for human leukocyte antigen and human CD4 receptors: implications for development of vaccines and therapeutics. J. Infect. Dis. 186:501510.
237. White, A.,, X. Ding,, J. C. vanderSpek,, J. R. Murphy,, and D. Ringe. 1998. Structure of the metal-ion-activated diphtheria toxin repressor/tox operator complex. Nature 394:502506.
238. Winston, D. J.,, D. V. Dudnick,, M. Chapin,, W. G. Ho,, R. P. Gale,, and W. J. Martin. 1983. Coagulase-negative staphylococcal bacteremia in patients receiving immunosuppressive therapy. Arch. Intern. Med. 143:3236.
239. Wylie, G. P.,, V. Rangachari,, E. A. Bienkiewicz,, V. Marin,, N. Bhattacharya,, J. F. Love,, J. R. Murphy,, and T. M. Logan. 2004. Prolylpeptide binding by the prokaryotic SH3-like domain of the diphtheria toxin repressor: a regulatory switch. Biochemistry 44:4051.
240. Xiao, Q.,, X. Jiang,, K. J. Moore,, Y. Shao,, H. Pi,, I. Dubail,, A. Charbit,, S. M. Newton,, and P. E. Klebba. 2011. Sortase independent and dependent systems for acquisition of haem and haemoglobin in Listeria monocytogenes. Mol. Microbiol. 80:15811597.
241. Xiong, A.,, V. K. Singh,, G. Cabrera,, and R. K. Jayaswal. 2000. Molecular characterization of the ferric-uptake regulator, Fur, from Staphylococcus aureus. Microbiology 146:659668.