10 Iron Uptake in Mycobacteria

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

10 Iron Uptake in Mycobacteria, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815783/9781555814687_Chap10-1.gif /docserver/preview/fulltext/10.1128/9781555815783/9781555814687_Chap10-2.gif


This chapter highlights both the well established and the yet poorly understood aspects of siderophoremediated iron acquisition in pathogenic and nonpathogenic mycobacteria, with a particular emphasis in the siderophore system of . The siderophore system is believed to play a crucial role in the procurement of a suitable iron supply to support bacterial multiplication in vivo and to be a key factor in the ability of this human pathogen to produce successful infections. The mycobacteria examined for iron-acquisition systems appear to rely on siderophores with high affinity for the ferric ion as the primary mechanism for iron acquisition. Transcription of genes of the exochelin (EXC) and mycobactin/carboxymycobactin (MBT/CMBT) systems is derepressed when the bacterium experiences iron limitations, thus leading to siderophore biosynthesis and siderophore-mediated iron uptake. Several Mycobacterium species produce two structurally related families of high-affinity Fe-binding siderophores, the MBTs and the CMBTs. Mutational analysis has conclusively linked the gene cluster to production of both MBTs and CMBTs. Mutational analysis has conclusively linked the gene cluster to production of both MBTs and CMBTs. Several Mycobacterium species that are normally found as environmental saprophytes release EXCs, the nonribosomally synthesized pentapeptidebased or hexapeptide-based siderophores, into the extracellular environment. More recently, analogues of salicyl-AMS have also been demonstrated to block MBT/CMBT biosynthesis and multiplication in iron-limiting conditions.

Citation: Quadri L. 2008. 10 Iron Uptake in Mycobacteria, p 167-183. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch10
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1.
Figure 1.

(A) Representative structures of mycobactins and carboxymycobactins from (left) and exochelin MS from (right). The primary difference between mycobactins and carboxymycobactins is in the substituent at R. Alternative alkyl substituents at R, R, and R are found in the siderophores of other species. (B) chromosomal loci containing the genes of the mycobactin/carboxymycobactin system (upper scheme) and chromosomal locus containing the genes of the exochelin MS system (bottom scheme). The gene map represents three distinct chromosomal loci (, , and from left to right) that are shown in their relative orientation and separated from each other by a wavy line. The functions of most of the genes depicted have been predicted but not experimentally confirmed. Genes encoding proteins involved in siderophore biosynthesis, ferrisiderophore uptake or receptor functions, and siderophore secretion are shown in black, vertical-line hatched, and diagonal-line hatched arrows, respectively. Genes of unknown functions are shown in white. IdeR binding sequences (confirmed or predicted) are marked with the symbol ⊕. Gene (84 bp), encoding tRNA-Leu and located between and , is not depicted. See text for information on individual genes.

Citation: Quadri L. 2008. 10 Iron Uptake in Mycobacteria, p 167-183. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2.
Figure 2.

(A) Mycobactin/carboxymycobactinmediated iron acquisition by intraphagosomal . The scheme shows alternatives for (ferri-) MBT/(ferri-)CMBT trafficking and delivery of iron to the bacterial cytoplasm. Under iron-limiting conditions, IdeR repression is decreased, and MBTs and CMBTs are synthesized by the siderophore biosynthesis machinery (SBM) and exported outside the cell by a yet unknown mechanism (a). Lipophilic MBTs have been shown to localize to the bacterial surface, perhaps at the membrane, where they can acquire Fe from ferri-CMBTs (b). MBTs at the cell surface have been suggested to function as ionophores to facilitate Fe transport across the membrane and/or act as transient stores of Fe (c). MBTs can also diffuse throughout the intracellular milieu of the macrophage and acquire Fe from cytoplasmic iron sources to form ferri-MBTs (d). Ferri-MBTs can diffuse in the intracellular milieu and accumulate in lipid droplets in contact with phagosomes (e). MBTs can sequester Fe from transferrin in the macrophage (f). CMBTs can acquire Fe from transferrin in vitro and are likely to do so in vivo as well (g). Porins may facilitate inward trafficking of ferri-CMBTs through the waxy cell envelope (h). Porins may also facilitate inward trafficking of ferri-MBTs. The IrtAB system has been proposed to transport ferri-CMBTs to the bacterial cytoplasm (i), but it is possible that the system transports ferri-MBTs as well. In the cytoplasm, an iron reductase (R) would release the iron from the chelates as Fe (j). It is also possible that a membrane reductase coupled with an iron transport system (FeT) removes Fe from ferrisiderophores at the extracellular side of the membrane and transports the Fe to the cytoplasm (k). Regardless of how Fe is delivered to the cytoplasm, it will be directed to synthesis of iron-containing compounds or temporarily stored (l). (B) Exochelin MS-mediated iron acquisition in . The MBT/CMBT system of , which is comparable to that of , is not shown. Under iron-limiting conditions, IdeR repression is decreased, and EXCs are synthesized and mobilized outside the cell, possibly through a mechanism involving ExiT (a). Secreted EXCs chelate Fe from environmental sources (b). Ferri-EXCs have been suggested to be bound at the cell envelope by the putative ferrisiderophore receptor FxuD, and possibly by a 29-kDa cell envelope protein not shown (c). Ferri-EXCs are likely to be transported to the cytoplasm by the FxuABC system (d), where an iron reductase would release the iron as Fe (e). Released Fe is directed to synthesis of iron-containing compounds or temporarily stored (f). (.)

Citation: Quadri L. 2008. 10 Iron Uptake in Mycobacteria, p 167-183. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3.
Figure 3.

(A) Salicylic acid (Sal) adenylation catalyzed by the adenylation domain (A) of MbtA and MbtAdependent transesterification of the salicyl moiety onto the prosthetic group of the aroyl carrier protein domain (ArCP) of the multifunctional peptide synthetase MbtB. (B) Salicyl-AMP and its nonhydrolyzable mimic salicyl-AMS. The difference between these two molecules is highlighted.

Citation: Quadri L. 2008. 10 Iron Uptake in Mycobacteria, p 167-183. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch10
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. Agranoff, D., and, S. Krishna. 2004. Metal ion transport and regulation in Mycobacterium tuberculosis. Front. Biosci. 9:29963006.
3. Andrews, S. C.,, A. K. Robinson, and, F. Rodriguez-Quinones. 2003. Bacterial iron homeostasis. FEMS Microbiol. Rev. 27:215237.
4. 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.
5. Bearden, S. W.,, J. D. Fetherston, and, R. D. Perry. 1997. Genetic organization of the yersiniabactin biosynthetic region and construction of avirulent mutants in Yersinia pestis. Infect. Immun. 65:16591668.
6. Bjarnason, J.,, C. M. Southward, and, M. G. Surette. 2003. Genomic profiling of ironresponsive genes in Salmonella enterica serovar typhimurium by high-throughput screening of a random promoter library. J. Bacteriol. 185:49734982.
7. Boukhalfa, H., and, A. L. Crumbliss. 2002. Chemical aspects of siderophore mediated iron transport. Biometals 15:325339.
8. Boyce, J. D.,, I. Wilkie,, M. Harper,, M. L. Paustian,, V. Kapur, and, B. Adler. 2002. Genomic scale analysis of Pasteurella multocida gene expression during growth within the natural chicken host. Infect. Immun. 70:68716879.
9. Braun, V. 2001. Iron uptake mechanisms and their regulation in pathogenic bacteria. Int. J. Med. Microbiol. 291:6779.
10. Brown, K. A., and, C. Ratledge. 1975. Iron transport in Mycobacterium smegmatis: ferrimycobactin reductase (NAD(P)H:ferrimycobactin oxidoreductase), the enzyme releasing iron from its carrier. FEBS Lett. 53:262266.
11. 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.
12. Card, G. L.,, N. A. Peterson,, C. A. Smith,, B. Rupp,, B. M. Schick, and, E. N. Baker. 2005. The crystal structure of Rv1347c, a putative antibiotic resistance protein from Mycobacterium tuberculosis, reveals a GCN5-related fold and suggests an alternative function in siderophore biosynthesis. J. Biol. Chem. 280:1397813986.
13. Carniel, E.,, A. Guiyoule,, I. Guilvout, and, O. Mercereau-Puijalon. 1992. Molecular cloning, iron-regulation and mutagenesis of the irp2 gene encoding HMWP2, a protein specific for the highly pathogenic Yersinia. Mol. Microbiol. 6:379388.
14. Cendrowski, S.,, W. MacArthur, and, P. Hanna. 2004. Bacillus anthracis requires siderophore biosynthesis for growth in macrophages and mouse virulence. Mol. Microbiol. 51:407417.
15. Chalut, C.,, L. Botella,, C. de Sousa-D’Auria,, C. Houssin, and, C. Guilhot. 2006. The nonredundant roles of two 4′-phosphopantetheinyl transferases in vital processes of Mycobacteria. Proc. Natl. Acad. Sci. USA 103:85118516.
16. Chipperfield, J. R., and, C. Ratledge. 2000. Salicylic acid is not a bacterial siderophore: a theoretical study. Biometals 13:165168.
17. 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.
18. Cole, S. T.,, R. Brosch,, J. Parkhill,, T. Garnier,, C. Churcher,, D. Harris,, S. V. Gordon,, K. Eiglmeier,, S. Gas,, C. E. Barry III,, F. Tekaia,, K. Badcock,, D. Basham,, D. Brown,, T. Chillingworth,, R. Connor,, R. Davies,, K. Devlin,, T. Feltwell,, S. Gentles,, N. Hamlin,, S. Holroyd,, T. Hornsby,, K. Jagels,, A. J. McLean,, S. Moule,, L. Murphy,, K. Oliver,, J. Osborne,, M. A. Quail,, M. A. Rajandream,, J. Rogers,, S. Rutter,, K. Seeger,, J. Skelton,, R. Squares,, S. Squares,, J. E. Sulston,, K. Taylor,, S. Whitehead, and, B. G. Barrell. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537544.
19. Cole, S. T.,, K. Eiglmeier,, J. Parkhill,, K. D. James,, N. R. Thomson,, P. R. Wheeler,, N. Honore,, T. Garnier,, C. Churcher,, D. Harris,, K. Mungall,, D. Basham,, D. Brown,, T. Chillingworth,, R. Connor,, R. M. Davies,, K. Devlin,, S. Duthoy,, T. Feltwell,, A. Fraser,, N. Hamlin,, S. Holroyd,, T. Hornsby,, K. Jagels,, C. Lacroix,, J. Maclean,, S. Moule,, L. Murphy,, K. Oliver,, M. A. Quail,, M. A. Rajandream,, K. M. Rutherford,, S. Rutter,, K. Seeger,, S. Simon,, M. Simmonds,, J. Skelton,, R. Squares,, S. Squares,, K. Stevens,, K. Taylor,, S. Whitehead,, J. R. Woodward, and, B. G. Barrell. 2001. Massive gene decay in the leprosy bacillus. Nature 409:10071011.
20. Cronje, L., and, L. Bornman. 2005. Iron overload and tuberculosis: a case for iron chelation therapy. Int. J. Tuberc. Lung Dis. 9:29.
21. Crosa, J. H. 1997. Signal transduction and transcriptional and posttranscriptional control of iron-regulated genes in bacteria. Microbiol. Mol. Biol. Rev. 61:319336.
22. Crosa, J. H., and, C. T. Walsh. 2002. Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol. Mol. Biol. Rev. 66:223249.
23. 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.
24. Darwin, K. H.,, S. Ehrt,, J. C. Gutierrez-Ramos,, N. Weich, and, C. F. Nathan. 2003. The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302:19631966.
25. De Voss, J. J.,, K. Rutter,, B. G. Schroeder, and, C. E. Barry III. 1999. Iron acquisition and metabolism by mycobacteria. J. Bacteriol. 181:44434451.
26. De Voss, J. J.,, K. Rutter,, B. G. Schroeder,, H. Su,, Y. Zhu, and, C. E. Barry III. 2000. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc. Natl. Acad. Sci. USA 97:12521257.
27. Der Vartanian, M.,, B. Jaffeux,, M. Contrepois,, M. Chavarot,, J. P. Girardeau,, Y. Bertin, and, C. Martin. 1992. Role of aerobactin in systemic spread of an opportunistic strain of Escherichia coli from the intestinal tract of gnotobiotic lambs. Infect. Immun. 60:28002807.
28. Dhungana, S.,, M. J. Miller,, L. Dong,, C. Ratledge, and, A. L. Crumbliss. 2003. Iron chelation properties of an extracellular siderophore exochelin MN. J. Am. Chem. Soc. 125:76547663.
29. Dhungana, S.,, C. Ratledge, and, A. L. Crumbliss. 2004. Iron chelation properties of an extracellular siderophore exochelin MS. Inorg. Chem. 43:62746283.
30. Dover, L. G., and, C. Ratledge. 1996. Identification of a 29-kDa protein in the envelope of Mycobacterium smegmatis as a putative ferri-exochelin receptor. Microbiology 142:15211530.
31. Drechsel, H., and, G. Winkelmann. 1997. Iron chelation and siderophores, p. 1–9. In G. Winkelmann and, C. J. Carrano (ed.), Transition Metals in Microbial Metabolism. Harwood Acad., Amsterdam, The Netherlands.
32. Du, L., and, B. Shen. 2001. Biosynthesis of hybrid peptide-polyketide natural products. Curr. Opin. Drug Discov. Devel. 4:215228.
33. Ducey, T. F.,, M. B. Carson,, J. Orvis,, A. P. Stintzi, and, D. W. Dyer. 2005. Identification of the ironresponsive genes of Neisseria gonorrhoeae by microarray analysis in defined medium. J. Bacteriol. 187:48654874.
34. Duerfahrt, T.,, K. Eppelmann,, R. Muller, and, M. A. Marahiel. 2004. Rational design of a bimodular model system for the investigation of heterocyclization in nonribosomal peptide biosynthesis. Chem. Biol. 11:261271.
35. 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.
36. Dussurget, O.,, M. Rodriguez, and, I. Smith. 1998. Protective role of the Mycobacterium smegmatis IdeR against reactive oxygen species and isoniazid toxicity. Tuber. Lung Dis. 79:99106.
37. 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 ironresponsive fxbA gene by the mycobacterial regulator IdeR. J. Bacteriol. 181:34023408.
38. Ernst, F. D.,, S. Bereswill,, B. Waidner,, J. Stoof,, U. Mader,, J. G. Kusters,, E. J. Kuipers,, M. Kist,, A. H. van Vliet, and, G. Homuth. 2005. Transcriptional profiling of Helicobacter pylori Furand iron-regulated gene expression. Microbiology 151:533546.
39. Fernandez, L.,, I. Marquez, and, J. A. Guijarro. 2004. Identification of specific in vivo-induced (ivi) genes in Yersinia ruckeri and analysis of ruckerbactin, a catecholate siderophore iron acquisition system. Appl. Environ. Microbiol. 70:51995207.
40. 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.
41. Fetherston, J. D.,, J. W. Lillard, Jr., and, R. D. Perry. 1995. Analysis of the pesticin receptor from Yersinia pestis: role in irondeficient growth and possible regulation by its siderophore. J. Bacteriol. 177:18241833.
42. Finking, R.,, A. Neumueller,, J. Solsbacher,, D. Konz,, G. Kretzschmar,, M. Schweitzer,, T. Krumm, and, M. A. Marahiel. 2003. Aminoacyl adenylate substrate analogues for the inhibition of adenylation domains of nonribosomal peptide synthetases. Chembiochem 4:903906.
43. Fiss, E. H.,, S. Yu, and, W. R. Jacobs, Jr. 1994. Identification of genes involved in the sequestration of iron in mycobacteria: the ferric exochelin biosynthetic and uptake pathways. Mol. Microbiol. 14:557569.
44. 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.
45. Gangaidzo, I. T.,, V. M. Moyo,, E. Mvundura,, G. Aggrey,, N. L. Murphree,, H. Khumalo,, T. Saungweme,, I. Kasvosve,, Z. A. Gomo,, T. Rouault,, J. R. Boelaert, and, V. R. Gordeuk. 2001. Association of pulmonary tuberculosis with increased dietary iron. J. Infect. Dis. 184:936939.
46. Gehring, A. M.,, E. DeMoll,, J. D. Fetherston,, I. Mori,, G. F. Mayhew,, F. R. Blattner,, C. T. Walsh, and, R. D. Perry. 1998a. Iron acquisition in plague: modular logic in enzymatic biogenesis of yersiniabactin by Yersinia pestis. Chem. Biol. 5:573586.
47. Gehring, A. M.,, I. I. Mori,, R. D. Perry, and, C. T. Walsh. 1998b. The nonribosomal peptide synthetase HMWP2 forms a thiazoline ring during biogenesis of yersiniabactin, an iron-chelating virulence factor of Yersinia pestis. Biochemistry 37:1163711650.
48. 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.
49. Gobin, J.,, C. H. Moore,, J. R. Reeve, Jr.,, D. K. Wong,, B. W. Gibson, and, M. A. Horwitz. 1995. Iron acquisition by Mycobacterium tuberculosis: isolation and characterization of a family of iron-binding exochelins. Proc. Natl. Acad. Sci. USA 92:51895193.
50. Gobin, J.,, D. K. Wong,, B. W. Gibson, and, M. A. Horwitz. 1999. Characterization of exochelins of the Mycobacterium bovis type strain and BCG substrains. Infect. Immun. 67:20352039.
51. Goetz, D. H.,, M. A. Holmes,, N. Borregaard,, M. E. Bluhm,, K. N. Raymond, and, R. K. Strong. 2002. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophoremediated iron acquisition. Mol. Cell. 10:10331043.
52. Gold, B.,, G. M. Rodriguez,, S. A. 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.
53. Grifantini, R.,, S. Sebastian,, E. Frigimelica,, M. Draghi,, E. Bartolini,, A. Muzzi,, R. Rappuoli,, G. Grandi, and, C. A. Genco. 2003. Identification of iron-activated and -repressed Fur-dependent genes by transcriptome analysis of Neisseria meningitidis group B. Proc. Natl. Acad. Sci. USA 100:95429547.
54. Hall, R. M., and, C. Ratledge. 1987. Exochelin-mediated iron acquisition by the leprosy bacillus, Mycobacterium leprae. J. Gen. Microbiol. 133:193199.
55. Hall, R. M.,, M. Sritharan,, A. J. Messenger, and, C. Ratledge. 1987. Iron transport in Mycobacterium smegmatis: occurrence of iron-regulated envelope proteins as potential receptors for iron uptake. J. Gen. Microbiol. 133:21072114.
56. Hall, R. M.,, P. R. Wheeler, and, C. Ratledge. 1983. Exochelin-mediated iron uptake into Mycobacterium leprae. Int. J. Lepr. Other Mycobact. Dis. 51:490494.
57. Harrison, A. J.,, M. Yu,, T. Gardenborg,, M. Middleditch,, R. J. Ramsay,, E. N. Baker, and, J. S. Lott. 2006. The structure of MbtI from Mycobacterium tuberculosis, the first enzyme in the biosynthesis of the siderophore mycobactin, reveals it to be a salicylate synthase. J. Bacteriol. 188:60816091.
58. Heesemann, J. 1987. Chromosomal-encoded siderophores are required for mouse virulence of enteropathogenic Yersinia species. FEMS Microbiol. Lett. 48:229233.
59. Henderson, D. P., and, S. M. Payne. 1994. Vibrio cholerae iron transport systems: roles of heme and siderophore iron transport in virulence and identification of a gene associated with multiple iron transport systems. Infect. Immun. 62:51205125.
60. Holmes, K.,, F. Mulholland,, B. M. Pearson,, C. Pin,, J. McNicholl-Kennedy,, J. M. Ketley, and, J. M. Wells. 2005a. Campylobacter jejuni gene expression in response to iron limitation and the role of Fur. Microbiology 151:243257.
61. Holmes, M. A.,, W. Paulsene,, X. Jide,, C. Ratledge, and, R. K. Strong. 2005b. Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Structure 13:2941.
62. Homuth, M.,, P. Valentin-Weigand,, M. Rohde, and, G. F. Gerlach. 1998. Identification and characterization of a novel extracellular ferric reductase from Mycobacterium paratuberculosis. Infect. Immun. 66:710716.
63. Hou, J. Y.,, J. E. Graham, and, J. E. Clark-Curtiss. 2002. Mycobacterium avium genes expressed during growth in human macrophages detected by selective capture of transcribed sequences (SCOTS). Infect. Immun. 70:37143726.
64. Jurado, R. L. 1997. Iron, infections, and anemia of inflammation. Clin. Infect. Dis. 25:888895.
65. Kato, L. 1985. Absence of mycobactin in Mycobacterium leprae; probably a microbe dependent microorganism implications. Indian J. Lepr. 57:5870.
66. Katoch, V. M. 2004. Infections due to non-tuberculous mycobacteria (NTM). Indian J. Med. Res. 120:290304.
67. Kjeldsen, L.,, J. B. Cowland, and, N. Borregaard. 2000. Human neutrophil gelatinase-associated lipocalin and homologous proteins in rat and mouse. Biochim. Biophys. Acta 1482:272283.
68. Krithika, R.,, U. Marathe,, P. Saxena,, M. Z. Ansari,, D. Mohanty, and, R. S. Gokhale. 2006. A genetic locus required for iron acquisition in Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 103:20692074.
69. LaMarca, B. B.,, W. Zhu,, J. E. Arceneaux,, B. R. Byers, and, M. D. Lundrigan. 2004. Participation of fad and mbt genes in synthesis of mycobactin in Mycobacterium smegmatis. J. Bacteriol. 186:374382.
70. Lane, S. J.,, P. S. Marshall,, R. J. Upton, and, C. Ratledge. 1998. Isolation and characterization of carboxymycobactins as the second extracellular siderophores in Mycobacterium smegmatis. Biometals 11:1320.
71. Lane, S. J.,, P. S. Marshall,, R. J. Upton,, C. Ratledge, and, M. Ewing. 1995. Novel extracellular mycobactins, the carboxymycobactins from Mycobacterium avium. Tetrahedron Lett. 36:41294132.
72. Lee, J.,, S. E. Kim,, J. Y. Lee,, S. Y. Kim,, S. U. Kang,, S. H. Seo,, M. W. Chun,, T. Kang,, S. Y. Choi, and, H. O. Kim. 2003. N-Alkoxysulfamide, N-hydroxysulfamide, and sulfamate analogues of methionyl and isoleucyl adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases. Bioorg. Med. Chem. Lett. 13:10871092.
73. Litwin, C. M.,, T. W. Rayback, and, J. Skinner. 1996. Role of catechol siderophore synthesis in Vibrio vulnificus virulence. Infect. Immun. 64:28342838.
74. Lounis, N.,, C. Truffot-Pernot,, J. Grosset,, V. R. Gordeuk, and, J. R. Boelaert. 2001. Iron and Mycobacterium tuberculosis infection. J. Clin. Virol. 20:123126.
75. Luo, M.,, E. A. Fadeev, and, J. T. Groves. 2005. Mycobactinmediated iron acquisition within macrophages. Nat. Chem. Biol. 1:149153.
76. MacCordick, H. J.,, J. J. Schleiffer, and, G. Duplatre. 1985. Radiochemical studies of iron binding and stability in ferrimycobactin S. Radiochim. Acta 38:4347.
77. Macham, L. P.,, M. C. Stephenson, and, C. Ratledge. 1977. Iron transport in Mycobacterium smegmatis: the isolation, purification and function of exochelin MS. J. Gen. Microbiol. 101:4149.
78. Marahiel, M. A.,, T. Stachelhaus, and, H. D. Mootz. 1997. Modular peptide synthetases involved in nonribosomal peptide synthesis. Chem. Rev. 97:26512674.
79. Merkal, R. S.,, W. G. McCullough, and, K. Takayama. 1981. Mycobactins, the state of the art. Bull. Inst. Pasteur 79:251259.
80. Merrell, D. S.,, L. J. Thompson,, C. C. Kim,, H. Mitchell,, L. S. Tompkins,, A. Lee, and, S. Falkow. 2003. Growth phase-dependent response of Helicobacter pylori to iron starvation. Infect. Immun. 71:65106525.
81. Messenger, A. J.,, R. M. Hall, and, C. Ratledge. 1986. Iron uptake processes in Mycobacterium vaccae R877R, a mycobacterium lacking mycobactin. J. Gen. Microbiol. 132:845852.
82. Meyer, J. M.,, P. Azelvandre, and, C. Georges. 1992. Iron metabolism in Pseudomonas: salicylic acid, a siderophore of Pseudomonas fluorescens CHAO. Biofactors 4:2327.
83. Miethke, M.,, H. Westers,, E. J. Blom,, O. P. Kuipers, and, M. A. Marahiel. 2006. Iron starvation triggers the stringent response and induces amino acid biosynthesis for bacillibactin production in Bacillus subtilis. J. Bacteriol. 188:86558657.
84. Morrison, N. E. 1995. Mycobacterium leprae iron nutrition: bacterioferritin, mycobactin, exochelin and intracellular growth. Int. J. Lepr. Other Mycobact. Dis. 63:8691.
85. Murakami, Y.,, S. Kato,, M. Nakajima,, M. Matsuoka,, H. Kawai,, K. Shin-Ya, and, H. Seto. 1996. Formobactin, a novel free radical scavenging and neuronal cell protecting substance from Nocardia sp. J. Antibiot. (Tokyo) 49:839–845.
86. Neilands, J. B. 1995. Siderophores: structure and function of microbial iron transport compounds. J. Biol. Chem. 270:2672326726.
87. Ochsner, U. A.,, P. J. Wilderman,, A. I. Vasil, and, M. L. Vasil. 2002. GeneChip expression analysis of the iron starvation response in Pseudomonas aeruginosa: identification of novel pyoverdine biosynthesis genes. Mol. Microbiol. 45:12771287.
88. Olakanmi, O.,, L. S. Schlesinger,, A. Ahmed, and, B. E. Britigan. 2002. Intraphagosomal Mycobacterium tuberculosis acquires iron from both extracellular transferrin and intracellular iron pools. Impact of interferon-gamma and hemochromatosis. J. Biol. Chem. 277:4972749734.
89. Olakanmi, O.,, L. S. Schlesinger,, A. Ahmed, and, B. E. Britigan. 2004. The nature of extracellular iron influences iron acquisition by Mycobacterium tuberculosis residing within human macrophages. Infect. Immun. 72:20222028.
90. Onwueme, K. C.,, C. J. Vos,, J. Zurita,, J. A. Ferreras, and, L. E. Quadri. 2005. The dimycocerosate ester polyketide virulence factors of mycobacteria. Prog. Lipid Res. 44:259302.
91. Palma, M.,, S. Worgall, and, L. E. Quadri. 2003. Transcriptome analysis of the Pseudomonas aeruginosa response to iron. Arch. Microbiol. 180:374379.
92. Palyada, K.,, D. Threadgill, and, A. Stintzi. 2004. Iron acquisition and regulation in Campylobacter jejuni. J. Bacteriol. 186:47144729.
93. Paustian, M. L.,, B. J. May, and, V. Kapur. 2001. Pasteurella multocida gene expression in response to iron limitation. Infect. Immun. 69:41094115.
94. Prakash, P.,, S. Yellaboina,, A. Ranjan, and, S. E. Hasnain. 2005. Computational prediction and experimental verification of novel IdeR binding sites in the upstream sequences of Mycobacterium tuberculosis open reading frames. Bioinformatics 21:21612166.
95. Quadri, L. E. N. 2000. Assembly of aryl-capped siderophores by modular peptide synthetases and polyketide synthases. Mol. Microbiol. 37:112.
96. Quadri, L. E. N. 2007. Strategic paradigm shifts in the antimicrobial drug discovery process of the 21st century. Infect. Disord. Drug Targets 7:230237.
97. Quadri, L. E. N.,, T. A. Keating,, H. M. Patel, and, C. T. Walsh. 1999. Assembly of the Pseudomonas aeruginosa nonribosomal peptide siderophore pyochelin: In vitro reconstitution of aryl-4,2-bisthiazoline synthetase activity from PchD, PchE, and PchF. Biochemistry 38:1494114954.
98. Quadri, L. E. N., and, C. Ratledge. 2005. Iron metabolism in the tubercle bacillus and other mycobacteria, p. 341-357. In S. T. Cole,, K. D. Eisenach,, D. N. McMurray, and, W. R. Jacobs, Jr. (ed.), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC.
99. Quadri, L. E. N.,, J. Sello,, T. A. Keating,, P. H. Weinreb, and, C. T. Walsh. 1998a. Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chem. Biol. 5:631645.
100. Quadri, L. E. N.,, P. H. Weinreb,, M. Lei,, M. M. Nakano,, P. Zuber, and, C. T. Walsh. 1998b. Characterization of Sfp, a Bacillus subtilis phosphopantetheinyl transferase for peptidyl carrier protein domains in peptide synthetases. Biochemistry 37:15851595.
101. Raghu, B.,, G. R. Sarma, and, P. Venkatesan. 1993. Effect of iron on the growth and siderophore production of mycobacteria. Biochem. Mol. Biol. Int. 31:341348.
102. Rakin, A.,, E. Saken,, D. Harmsen, and, J. Heesemann. 1994. The pesticin receptor of Yersinia enterocolitica: a novel virulence factor with dual function. Mol. Microbiol. 13:253263.
103. Ratledge, C., and, L. G. Dover. 2000. Iron metabolism in pathogenic bacteria. Annu. Rev. Microbiol. 54:881941.
104. Ratledge, C., and, M. Ewing. 1996. The occurrence of carboxymycobactin, the siderophore of pathogenic mycobacteria, as a second extracellular siderophore in Mycobacterium smegmatis. Microbiology 142:22072212.
105. Ratledge, C.,, P. V. Patel, and, J. Mundy. 1982. Iron transport in Mycobacterium smegmatis: the location of mycobactin by electron microscopy. J. Gen. Microbiol. 128:15591565.
106. Ratledge, C., and, G. A. Snow. 1974. Isolation and structure of nocobactin NA, a lipid-soluble iron-binding compound from Nocardia asteroides. Biochem. J. 139:407413.
107. Ratledge, C., and, F. G. Winder. 1962. The accumulation of salicylic acid by mycobacteria during growth on an irondeficient medium. Biochem. J. 84:501506.
108. Register, K. B.,, T. F. Ducey,, S. L. Brockmeier, and, D. W. Dyer. 2001. Reduced virulence of a Bordetella bronchiseptica siderophore mutant in neonatal swine. Infect. Immun. 69:21372143.
109. Rodriguez, G. M. 2006. Control of iron metabolism in Mycobacterium tuberculosis. Trends Microbiol. 14:320327.
110. Rodriguez, G. M., and, I. Smith. 2003. Mechanisms of iron regulation in mycobacteria: role in physiology and virulence. Mol. Microbiol. 47:14851494.
111. 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.
112. 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.
113. Sassetti, C. M.,, D. H. Boyd, and, E. J. Rubin. 2003. Genes required for mycobacterial growth defined by high density mutagenesis. Mol. Microbiol. 48:7784.
114. Schaible, U. E.,, H. L. Collins,, F. Priem, and, S. H. Kaufmann. 2002. Correction of the iron overload defect in β-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J. Exp. Med. 196:15071513.
115. Schnappinger, D.,, S. Ehrt,, M. I. Voskuil,, Y. Liu,, J. A. Mangan,, I. M. Monahan,, G. Dolganov,, B. Efron,, P. D. Butcher,, C. Nathan, and, G. K. Schoolnik. 2003. Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: Insights into the phagosomal environment. J. Exp. Med. 198:693704.
116. Sharman, G. J.,, D. H. Williams,, D. F. Ewing, and, C. Ratledge. 1995a. Determination of the structure of exochelin MN, the extracellular siderophore from Mycobacterium neoaurum. Chem. Biol. 2:553561.
117. Sharman, G. J.,, D. H. Williams,, D. F. Ewing, and, C. Ratledge. 1995b. Isolation, purification and structure of exochelin MS, the extracellular siderophore from Mycobacterium smegmatis. Biochem. J. 305:187196.
118. Singh, A. K.,, L. M. McIntyre, and, L. A. Sherman. 2003. Microarray analysis of the genome-wide response to iron deficiency and iron reconstitution in the cyanobacterium Synechocystis sp. PCC 6803. Plant Physiol. 132:18251839.
119. Snow, G. A. 1970. Mycobactins: iron-chelating growth factors from mycobacteria. Bacteriol. Rev. 34:99125.
120. Sokol, P. A.,, P. Darling,, D. E. Woods,, E. Mahenthiralingam, and, C. Kooi. 1999. Role of ornibactin biosynthesis in the virulence of Burkholderia cepacia: characterization of pvdA, the gene encoding L-ornithine N(5)-oxygenase. Infect. Immun. 67:44434455.
121. Somu, R. V.,, H. Boshoff,, C. Qiao,, E. M. Bennett,, C. E. Barry III, and, C. C. Aldrich. 2006. Rationally designed nucleoside antibiotics that inhibit siderophore biosynthesis of Mycobacterium tuberculosis. J. Med. Chem. 49:3134.
122. Stephenson, M. C., and, C. Ratledge. 1979. Iron transport in Mycobacterium smegmatis: uptake of iron from ferriexochelin. J. Gen. Microbiol. 110:193202.
123. Stephenson, M. C., and, C. Ratledge. 1980. Specificity of exochelins for iron transport in three species of mycobacteria. J. Gen. Microbiol. 116:521523.
124. Takase, H.,, H. Nitanai,, K. Hoshino, and, T. Otani. 2000. Impact of siderophore production on Pseudomonas aeruginosa infections in immunosuppressed mice. Infect. Immun. 68:18341839.
125. Talaat, A. M.,, R. Lyons,, S. T. Howard, and, S. A. Johnston. 2004. The temporal expression profile of Mycobacterium tuberculosis infection in mice. Proc. Natl. Acad. Sci. USA 101:46024607.
126. Timm, J.,, F. A. Post,, L. G. Bekker,, G. B. Walther,, H. C. Wainwright,, R. Manganelli,, W. T. Chan,, L. Tsenova,, B. Gold,, I. Smith,, G. Kaplan, and, J. D. McKinney. 2003. Differential expression of iron-, carbon-, and oxygen-responsive mycobacterial genes in the lungs of chronically infected mice and tuberculosis patients. Proc. Natl. Acad. Sci. USA 100:1432114326.
127. Todd, J. D.,, G. Sawers, and, A. W. Johnston. 2005. Proteomic analysis reveals the wide-ranging effects of the novel, ironresponsive regulator RirA in Rhizobium leguminosarum bv. viciae. Mol. Genet. Genomics 273:197206.
128. Touati, D. 2000. Iron and oxidative stress in bacteria. Arch. Biochem. Biophys. 373:16.
129. Wagner, D.,, J. Maser,, B. Lai,, Z. Cai,, C. E. Barry III,, K. Honer Zu Bentrup,, D. G. Russell, and, L. E. Bermudez. 2005. Elemental analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-containing phagosomes indicates pathogen-induced microenvironments within the host cell’s endosomal system. J. Immunol. 174:14911500.
130. Walsh, C. T. 2004. Polyketide and nonribosomal peptide antibiotics: modularity and versatility. Science 303:18051810.
131. Walsh, C. T.,, A. M. Gehring,, P. H. Weinreb,, L. E. Quadri, and, R. S. Flugel. 1997. Post-translational modification of polyketide and nonribosomal peptide synthases. Curr. Opin. Chem. Biol. 1:309315.
132. Wan, X. F.,, N. C. Verberkmoes,, L. A. McCue,, D. Stanek,, H. Connelly,, L. J. Hauser,, L. Wu,, X. Liu,, T. Yan,, A. Leaphart,, R. L. Hettich,, J. Zhou, and, D. K. Thompson. 2004. Transcriptomic and proteomic characterization of the Fur modulon in the metal-reducing bacterium Shewanella oneidensis. J. Bacteriol. 186:83858400.
133. Wandersman, C., and, P. Delepelaire. 2004. Bacterial iron sources: from siderophores to hemophores. Annu. Rev. Microbiol. 58:611647.
134. Ward, C. G.,, J. J. Bullen, and, H. J. Rogers. 1996. Iron and infection: new developments and their implications. J. Trauma 41:356364.
135. Wehrl, W.,, T. F. Meyer,, P. R. Jungblut,, E. C. Muller, and, A. J. Szczepek. 2004. Action and reaction: Chlamydophila pneumoniae proteome alteration in a persistent infection induced by iron deficiency. Proteomics 4:29692981.
136. Weinberg, E. D. 1978. Iron and infection. Microbiol. Rev. 42:4566.
137. Weinberg, E. D. 1993. The development of awareness of iron-withholding defense. Perspect. Biol. Med. 36:215221.
138. Williams, D. L.,, M. Torrero,, P. R. Wheeler,, R. W. Truman,, M. Yoder,, N. Morrison,, W. R. Bishai, and, T. P. Gillis. 2004. Biological implications of Mycobacterium leprae gene expression during infection. J. Mol. Microbiol. Biotechnol. 8:5872.
139. Wong, D. K.,, J. Gobin,, M. A. Horwitz, and, B. W. Gibson. 1996. Characterization of exochelins of Mycobacterium avium: evidence for saturated and unsaturated and for acid and ester forms. J. Bacteriol. 178:63946398.
140. Wooldridge, K. G., and, P. H. Williams. 1993. Iron uptake mechanisms of pathogenic bacteria. FEMS Microbiol. Rev. 12:325348.
141. Xu, S., and, P. Venge. 2000. Lipocalins as biochemical markers of disease. Biochim. Biophys. Acta 1482:298307.
142. Yancey, R. J.,, S. A. Breeding, and, C. E. Lankford. 1979. Enterochelin (enterobactin): virulence factor for Salmonella typhimurium. Infect. Immun. 24:174180.
143. Yellaboina, S.,, S. Ranjan,, V. Vindal, and, A. Ranjan. 2006. Comparative analysis of iron regulated genes in mycobacteria. FEBS Lett. 580:25672576.
144. Yu, S.,, E. Fiss, and, W. R. Jacobs, Jr. 1998. Analysis of the exochelin locus in Mycobacterium smegmatis: biosynthesis genes have homology with genes of the peptide synthetase family. J. Bacteriol. 180:46764685.
145. Zhu, W.,, J. E. Arceneaux,, M. L. Beggs,, B. R. Byers,, K. D. Eisenach, and, M. D. Lundrigan. 1998. Exochelin genes in Mycobacterium smegmatis: identification of an ABC transporter and two non-ribosomal peptide synthetase genes. Mol. Microbiol. 29:629639.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error