Targeting iron assimilation to develop new antibacterials

Expert Opinion on Drug Discovery

Volumn 7, Issue 9, 2012, Pages 831-847

  Foley, Timothy L ^a   Simeonov, Anton ^a  

^a NATIONAL INSTITUTES OF HEALTH   (United States)

Author keywords

antibacterial; antibiotic; chelation therapy; high throughput screening; iron assimilation; siderophore

Indexed keywords

ANTIBIOTIC AGENT; CICLOPIROX; DEFERASIROX; DEFERIPRONE; HEME; IRON; SIDEROPHORE;

ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; BACTERIAL INFECTION; BINDING AFFINITY; CHELATION THERAPY; DRUG CONJUGATION; DRUG MECHANISM; DRUG POTENCY; DRUG TARGETING; HOMEOSTASIS; HOST PATHOGEN INTERACTION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; REVIEW;

ANTI-BACTERIAL AGENTS; BACTERIA; BACTERIAL INFECTIONS; CHELATION THERAPY; DRUG DISCOVERY; HUMANS; IRON; SIDEROPHORES;

EID: 84865529072     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2012.708335     Document Type: Review

References (92)

1. Power E. Impact of antibiotic restrictions: the pharmaceutical perspective. Clin Microbiol Infect 2006;12:25-34
2. Norrby R, Powell M. The bacterial challenge: time to react. European Centre for Disease Prevention and Control; Stockholm: 2009
3. Choffnes ER, Relman DA, Mack A. Antibiotic resistance: implications for global health and novel intervention strategies. National Academies Press; Washington, D.C: 2010
4. Bad bugs, no drugs: as antibiotic discovery stagnates⋯ a public health crisis brews. Infectious Disease Society of America; Alexandria, VA: 2004
5. Gilbert DN, Guidos RJ, Boucher HW, et al. The 10 x'20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis 2010;50(8):1081-3
6. Boucher HW. Challenges in anti-infective development in the era of bad bugs, no drugs: a regulatory perspective using the example of bloodstream infection as an indication. Clin Infect Dis 2010;50:S4-9
7. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! an update from the infectious diseases society of America. Clin Infect Dis 2009;48(1):1-12
8. Guidos RJ, Spellberg B, Blaser M, et al. Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis 2011;52:S397-428
9. Neilands JB. Iron absorption and transport in microorganisms. Annu Rev Nutr 1981;1:27-46
10. Ratledge C. Iron metabolism and infection. Food Nutr Bull 2007;28(4 Suppl):S515-23
11. Ratledge C, Dover LG. Iron metabolism in pathogenic bacteria. Annu Rev Microbiol 2000;54:881-941
12. Crosa JH. Signal transduction and transcriptional and posttranscriptional control of iron-regulated genes in bacteria. Microbiol Mol Biol Rev 1997;61(3):319-36
13. Escolar L, Perez-Martin J, de Lorenzo V. Opening the iron box: transcriptional metalloregulation by the fur protein. J Bacteriol 1999;181(20):6223-9
14. Banin E, Vasil ML, Greenberg EP. Iron and Pseudomonas aeruginosa biofilm formation. Proc Natl Acad Sci USA 2005;102(31):11076-81
15. Hancock V, Dahl M, Klemm P. Abolition of biofilm formation in urinary tract escherichia coli and klebsiella isolates by metal interference through competition for fur. Appl Environ Microbiol 2010;76(12):3836-41
16. Pollack JR, Neilands JB. Enterobactin, an iron transport compound from salmonella typhimurium. Biochem Biophys Res Commun 1970;38(5):989-92
17. Furrer JL, Sanders DN, Hook-Barnard IG, et al. Export of the siderophore enterobactin in Escherichia coli: involvement of a 43 kDa membrane exporter. Mol Microbiol 2002;44(5):1225-34
18. Bister B, Bischoff D, Nicholson GJ, et al. The structure of salmochelins: C-glucosylated enterobactins of salmonella enterica. Biometals 2004;17(4):471-81
19. Fischbach MA, Lin HN, Liu DR, et al. In vitro characterization of IroB, a pathogen-associated C-glycosyltransferase. Proc Natl Acad Sci USA 2005;102(3):571-6
20. Lin H, Fiscchbach MA, Liu DR, et al. In vitro characterization of salmochelin and enterobactin trilactone hydrolases IroD, IroE, and Fes. J Am Chem Soc 2005;127(31):11075-84
21. Crouch M-LV, Castor M, Karlinsey JE, et al. Biosynthesis and IroC-dependent export of the siderophore salmochelin are essential for virulence of Salmonella enterica serovar Typhimurium. Mol Microbiol 2008;67(5):971-83
22. Wiener MC, Horanyi PS. How hydrophobic molecules traverse the outer membranes of Gram-negative bacteria. Proc Natl Acad Sci USA 2011;108(27):10929- 30
23. Caza M, Lepine F, Milot S, et al. Specific roles of the iroBCDEN genes in virulence of an avian pathogenic Eschetichia coli O78 strain and in production of salmochelins. Infect Immun 2008;76(8):3539-49
24. Abergel RJ, Zawadzka AM, Hoette TM, et al. Enzymatic hydrolysis of trilactone siderophores: where chiral recognition occurs in enterobactin and bacillibactin iron transport. J Am Chem Soc 2009;131(35):12682-92
25. Larsen NA, Lin H, Wei R, et al. Structural characterization of enterobactin hydrolase IroE. Biochemistry 2006;45(34):10184-90
26. Wilks A, Burkhard KA. Heme and virulence: how bacterial pathogens regulate, transport and utilize heme. Nat Prod Rep 2007;24(3):511-22
27. Gkouvatsos K, Papanikolaou G, Pantopoulos K. Regulation of iron transport and the role of transferrin. Biochim Biophys Acta Gen Subj 2012;1820(3):188-202
28. Siddique A, Kowdley KV. Review article: the iron overload syndromes. Aliment Pharmacol Ther 2012;35(8):876-93
29. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102(3):783-8
30. Abril Garcia-Montoya I, Siqueiros Cendon T, Arevalo-Gallegos S, et al. Lactoferrin a multiple bioactive protein: an overview. Biochim Biophys Acta Gen Subj 2012;1820(3):226-36
31. Crowley RC, Leigh JA, Ward PN, et al. Differential protein expression in streptococcus uberis under planktonic and biofilm growth conditions. Appl Environ Microbiol 2011;77(1):382-4
32. Kamiya H, Ehara T, Matsumoto T. Inhibitory effects of lactoferrin on biofilm formation in clinical isolates of Pseudomonas aeruginosa. J Infect Chemother 2012;18(1):47-52
33. Wandersman C, Delepelaire P. Bacterial iron sources: from siderophores to hemophores. Annu Rev Microbiol 2004;58:611-47
34. Modun B, Williams P. The staphylococcal transferrin-binding protein is a cell wall glyceraldehyde-3-phosphate dehydrogenase. Infect Immun 1999;67(3):1086-92
35. Taylor JM, Heinrichs DE. Transferrin binding in Staphylococcus aureus: involvement of a cell wall-anchored protein. Mol Microbiol 2002;43(6):1603-14
36. Fischbach MA, Lin H, Liu DR, et al. How pathogenic bacteria evade mammalian sabotage in the battle for iron. Nat Chem Biol 2006;2(3):132-8
37. Konopka K, Neilands JB. Effect of serum albumin on the siderophore-mediated utilization of transferrin iron. Biochemistry 1984;23(10):2122-7
38. Smith KD. Iron metabolism at the host pathogen interface: lipocalin 2 and the pathogen-associated iroA gene cluster. Int J Biochem Cell Biol 2007;39(10):1776-80
39. Borregaard N, Cowland JB. Neutrophil gelatinase-associated lipocalin, a siderophore-binding eukaryotic protein. Biometals 2006;19(2):211-15
40. Goetz DH, Holmes MA, Borregaard N, et al. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell 2002;10(5):1033-43
41. Sorsa LJ, Dufke S, Heesemann J, et al. Characterization of an iroBCDEN gene cluster on a transmissible plasmid of uropathogenic Escherichia coli: evidence for horizontal transfer of a chromosomal virulence factor. Infect Immun 2003;71(6):3285-93
42. Fischbach MA, Lin H, Zhou L, et al. The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2. Proc Natl Acad Sci USA 2006;103(44):16502-7
43. Johnson JR, Russo TA. Uropathogenic Escherichia coli as agents of diverse non-urinary tract extraintestinal infections. J Infect Dis 2002;186(6):859-64
44. Johnson JR, Russo TA. Extraintestinal pathogenic Escherichia coli: "The other bad E coli". J Lab Clin Med 2002;139(3):155-62
45. Kovacevic Z, Kalinowski DS, Lovejoy DB, et al. The medicinal chemistry of novel iron chelators for the treatment of cancer. Curr Top Med Chem 2011;11(5):483-99
46. Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med 2005;353(11):1135-46
47. Nick H, Acklin P, Lattmann R, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem 2003;10(12):1065-76
48. Brock JH, Liceaga J, Kontoghiorghes GJ. The effect of synthetic iron chelators on bacterial growth in human serum. FEMS Microbiol Immunol 1988;1(1):55-60
49. Hartzen SH, Frimodtmoller N, Thomsen VF. The antibacterial activity of a siderophore. 2. The influence of deferoxamine alone and combined with ascorbic acid on the activity of antibiotics against Staphyloccocus aureus. APMIS 1991;99(10):879-86
50. Zurlo MG, Destefano P, Borgnapignatti C, et al. Survival and causes of death in thalassemia major. Lancet 1989;2(8653):27-30
51. Zarember KA, Cruz AR, Huang C-Y, et al. Antifungal activities of natural and synthetic iron chelators alone and in combination with azole and polyene antibiotics against aspergillus fumigatus. Antimicrob Agents Chemother 2009;53(6):2654-6
52. Ibrahim AS, Edwards JE, Fu Y, et al. Deferiprone iron chelation as a novel therapy for experimental mucormycosis. J Antimicrob Chemother 2006;58(5):1070-3
53. Ibrahim AS, Gebermariam T, Fu Y, et al. The iron chelator deferasirox protects mice from mucormycosis through iron starvation. J Clin Investig 2007;117(9):2649-57
54. Spellberg B, Andes D, Perez M, et al. Safety and outcomes of open-label deferasirox iron chelation therapy for mucormycosis. Antimicrob Agents Chemother 2009;53(7):3122-5
55. Reed C, Ibrahim A, Edwards JE, et al. Deferasirox, an iron-chelating agent, as salvage therapy for rhinocerebral mucormycosis. Antimicrob Agents Chemother 2006;50(11): 3968-9
56. Spellberg B, Ibrahim AS, Chin-Hong PV, et al. The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial. Antimicrob Agents Chemother 2012;67(3):715-22
57. Kerbarh O, Bulloch EM, Payne RJ, et al. Mechanistic and inhibition studies of chorismate-utilizing enzymes. Biochem Soc Trans 2005;33(Pt 4):763-6
58. Manos-Turvey A, Bulloch EM, Rutledge PJ, et al. Inhibition studies of mycobacterium tuberculosis salicylate synthase (MbtI). ChemMedChem 2010;5(7):1067-79
59. Vasan M, Neres J, Williams J, et al. Inhibitors of the salicylate synthase (MbtI) from mycobacterium tuberculosis discovered by high-throughput screening. ChemMedChem 2010;5(12):2079-87
60. Finking R, Neumuller A, Solsbacher J, et al. Aminoacyl adenylate substrate analogues for the inhibition of adenylation domains of nonribosomal peptide synthetases. ChemBioChem 2003;4(9):903-6
61. Ferreras JA, Ryu JS, Di Lello F, et al. Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat Chem Biol 2005;1(1):29-32
62. Duckworth BP, Nelson KM, Aldrich CC. Adenylating enzymes in mycobacterium tuberculosis as drug targets. Curr Top Med Chem 2012;12(7):766-96
63. Gupte A, Boshoff HI, Wilson DJ, et al. Inhibition of siderophore biosynthesis by 2-triazole substituted analogues of 5'-O-N-(Salicyl)sulfamoyl adenosine: antibacterial nucleosides effective against mycobacterium tuberculosis. J Med Chem 2008;51(23):7495-507
64. Qiao CH, Gupte A, Boshoff HI, et al. 5 '-O-(N-Acyl)sulfamoyl adenosines as antitubercular agents that inhibit MbtA: an adenylation enzyme required for siderophore biosynthesis of the mycobactins. J Med Chem 2007;50(24):6080-94
65. Gupte A, Subramanian M, Remmel RP, et al. Synthesis of deuterium-labelled 5 '-O-N-(Salicyl)sulfamoyl adenosine (Sal-AMS-d(4)) as an internal standard for quantitation of Sal-AMS. J Labelled Compounds Radiopharm 2008;51(1-2):118-22
66. Drake EJ, Duckworth BP, Neres J, et al. Biochemical and structural characterization of bisubstrate inhibitors of BasE, the self-standing nonribosomal peptide synthetase adenylate-forming enzyme of acinetobactin synthesis. Biochemistry 2010;49(43):9292-305
67. Gulick AM. Conformational dynamics in the Acyl-CoA synthetases, adenylation domains of non-ribosomal peptide synthetases, and firefly luciferase. ACS Chem Biol 2009;4(10):811-27
68. Auld DS, Thorne N, Maguire WF, et al. Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression. Proc Natl Acad Sci USA 2009;106(9):3585-90
69. Auld DS, Lovell S, Thorne N, et al. Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124. Proc Natl Acad Sci USA 2010;107(11):4878-83
70. Drake EJ, Gulick AM. Structural characterization and high-throughput screening of inhibitors of PvdQ, an NTN hydrolase involved in pyoverdine synthesis. ACS Chem Biol 2011;6(11):1277-86
71. Hancock REW. The bacterial outer membrane as a drug barrier. Trends Microbiol 1997;5(1):37-42
72. Braun V, Pramanik A, Gwinner T, et al. Sideromycins: tools and antibiotics. Biometals 2009;22(1):3-13
73. Pramanik A, Stroeher UH, Krejci J, et al. Albomycin is an effective antibiotic, as exemplified with yersinia enterocolitica and Streptococcus pneumoniae. Int J Med Microbiol 2007;297(6):459-69
74. Miller MJ, Zhu H, Xu Y, et al. Utilization of microbial iron assimilation processes for the development of new antibiotics and inspiration for the design of new anticancer agents. Biometals 2009;22(1):61-75
75. Ji C, Juarez-Hernandez RE, Miller MJ. Exploiting bacterial iron acquisition: siderophore conjugates. Future Med Chem 2012;4(3):297-313
76. Miller MJ, Walz AJ, Zhu H, et al. Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria. J Am Chem Soc 2011;133(7):2076-9
77. Flanagan ME, Brickner SJ, Lall M, et al. Preparation, gram-negative antibacterial activity, and hydrolytic stability of novel siderophore-conjugated monocarbam diols. Acs Med Chem Lett 2011;2(5):385-90
78. Higgins PG, Stefanik D, Page MGP, et al. In vitro activity of the siderophore monosulfactam BAL30072 against meropenem-non-susceptible acinetobacter baumannii. J Antimicrob Chemother 2012;67(5):1167-9
79. Mima T, Kvitko BH, Rholl DA, et al. In vitro activity of BAL30072 against burkholderia pseudomallei. Int J Antimicrob Agents 2011;38(2):157-9
80. Mushtaq S, Warner M, Livermore D. Activity of the siderophore monobactam BAL30072 against multiresistant non-fermenters. J Antimicrob Chemother 2010;65(2):266-70
81. Page MG, Dantier C, Desarbre E. In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant gram-negative bacilli. Antimicrob Agents Chemother 2010;54(6):2291-302
82. Page MGP, Desarbre E, Gebhardt K, et al. Synthesis and antimicrobial activity of the novel siderophore sulfactam BAL30072. Int J Infect Dis 2011;15:S17-17
83. Pharmaceutica B. Basilea announces conclusion of BAL30072 phase I multiple ascending dose study. Basel, Switzerland: 2011
84. Stojiljkovic I, Evavold BD, Kumar V. Antimicrobial properties of porphyrins. Expert Opin Investig Drugs 2001;10(2):309-20
85. Stojiljkovic I, Kumar V, Srinivasan N. Non-iron metalloporphyrins: potent antibacterial compounds that exploit haem/Hb uptake systems of pathogenic bacteria. Mol Microbiol 1999;31(2):429-42
86. Reniere ML, Torres VJ, Skaar EP. Intracellular metalloporphyrin metabolism in Staphylococcus aureus. Biometals 2007;20(3-4):333-45
87. Furci LM, Lopes P, Eakanunkul S, et al. Inhibition of the bacterial heme oxygenases from Pseudomonas aeruginosa and Neisseria meningitidis: novel antimicrobial targets. J Med Chem 2007;50(16):3804-13
88. Caza M, Lepine F, Dozois CM. Secretion, but not overall synthesis, of catecholate siderophores contributes to virulence of extraintestinal pathogenic Escherichia coli. Mol Microbiol 2011;80(1):266-82
89. Pace NR. A molecular view of microbial diversity and the biosphere. Science 1997;276(5313):734-40
90. Payne DJ, Gwynn MN, Holmes DJ, et al. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 2007;6(1):29-40
91. Broetz-Oesterhelt H, Sass P. Postgenomic strategies in antibacterial drug discovery. Future Microbiol 2010;5(10):1553-79
92. Miethke M, Marahiel MA. Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 2007;71(3):413-51