NATURAL IRON SEQUESTERING AGENTS: THEIR ROLES IN NATURE AND THERAPEUTIC POTENTIAL
Iron is one of the essential elements involved in many cellular processes that are necessary for life, including oxygen sensing, oxygen transport, electron transfer, energy metabolism, DNA synthesis etc. Although, iron is not readily available in the naturally available iron III form, microorganisms have evolved to produce smaller high affinity chelating small organic molecules called siderophores for its acquisition. The study of siderophores has opened up investigations of small-molecule inhibitors, which can hinder the biosynthesis of siderophores and thereby suppress the growth and virulence of bacteria in iron-limiting backgrounds. One of the most important applications of siderophores is selective drug delivery to defeat drug-resistant bacteria. It uses the iron transport capabilities of siderophores in carrying drugs/molecules into cells, synthetic through conjugates between siderophores and antimicrobial agents forming sideromycins. Some siderophore such as Desferrioxamine B have been found to be useful in the treatment of malaria caused by Plasmodiumfalciparum through intracellular iron depletion mechanisms. Importantly, iron overload diseases can be efficiently treated with siderophore based drugs as they can quench iron effectively. Moreover, siderophores such as dexrazoxane, desferriexochelins, isonicotinoyl hydrazine derivatives are being used in cancer therapy, as they prevent the formation of free radicals by reducing iron and retard the tumor growth by disturbing the iron regulation in tumor cells. In addition to bacterial siderophores, it is reported that plant-derived polyphenols, phenolic acids,and flavonoid compounds show siderophores like activity scavenging iron which gives rise to their antioxidant and anticancer activity.
2. Gulick AM. Ironing out a new siderophore synthesis strategy. Nat Chem Biol 2009;5:143-4.
3. Karunaratne V, Hoveyda HR, Orvig C. General method for the synthesis of trishydroxamic acids. Tetra Lett 1992;33:1827-30.
4. Xiao G, Van der Helm D, Hider RC, Dobbin PS. Structure-stability relationships of 3-hydroxypyridin-4-one complexes. J Chem Soc Dalton Trans 1992;3265-71. doi: 10.1039/DT9920003265. [Article in Press]
5. Miethke M, Marahiel MA. Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 2007;71:413-51.
6. Hantke K. Iron and metal regulation in bacteria. Curr Opin Microbiol 2001;4:172-7.
7. Ahmed E, HolmstrÃ¶m SJM. Siderophores in environmental research: roles and applications. Microbiol Biotechnol 2014;7:196-208.
8. Martin JH. Glacial-interglacial CO2 change: The Iron Hypothesis. Paleoceanography 1990;5:1-13.
9. Telford JR, Raymond KN. Coordination chemistry of the amonabactins, bis(catecholate) siderophores from Aeromonas hydrophila. Inorg Chem 1998;37:4578-83.
10. Holmes MA, Paulsene W, Jide X, Ratledge C, Strong RK. Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Structure 2005;13:29-41.
11. Brown KA, Ratledge C. The effect of p-aminosalicyclic acid on iron transport and assimilation in mycobacteria. Biochim Biophys Acta 1975;385:207-20.
12. Payne RJ, Kerbarh O, Miguel RN, Abell AD, Abell C. Inhibition studies on salicylate synthase. Org Biomol Chem 2005;3:1825-7.
13. Shales DM, Projan SJ, Edwards JEJ. Antibiotic discovery: state of the state. ASM News 2004;70:275-81.
14. Mollmann U, Heinisch L, Bauernfeind A, Kohler T, Ankel-Fuchs D. Siderophores as drug delivery agents: application of the "Trojan Horse" strategy. Biometals 2009;22:615-24.
15. Arisawa M, Sekine Y, Shimizu S, Takano H, Angehrn P, Then RL. In vitro and in vivo evaluation of Ro 09-1428, a new parenteral cephalosporin with high antipseudomonal activity. Antimicrob Agents Chemother 1991;35:653-9.
16. Sackmann W, Reusser P, Neipp L, Kradolfer F, Gross F. Ferrimycin A, a new iron-containing antibiotic. Antibiot Chemother (Northfield Ill) 1962;12:34-45.
17. Pramanik A, Braun V. Albomycin uptake via a ferric hydroxamate transport system of Streptococcus pneumoniae R6. J Bacteriol 2006;188:3878-86.
18. Braun V, Pramanik A, Gwinner T, Koberle M, Bohn E. Sideromycins: tools and antibiotics. Biometals 2009;22:3-13.
19. Mislin GLA, Schalk IJ. Siderophore-dependent iron uptake systems as gates for antibiotic Trojan horse strategies against Pseudomonas aeruginosa. Metallomics 2014;6:408-20.
20. Ghosh A,Ghosh M, Niu C, Malouin F, Moellmann U, Miller MJ. Iron transport-mediated drug delivery using mixed-ligand siderophore-beta-lactam conjugates. Chem Biol 1996;3:1011-9.
21. Scott MD, Ranz A, Kuypers FA, Lubin BH, Meshnick SR. Parasite uptake of desferroxamine: a prerequisite for antimalarial activity. Br J Haematol 1990;75:598-602.
22. Ghosh M, Lambert LJ, Huber PW, Miller MJ. Synthesis, bioactivity, and DNA-cleaving ability of desferrioxamine B-nalidixic acid and anthraquinone carboxylic acid conjugates. Bioorg Med Chem Lett 1995;5:2337-40.
23. Kontoghiorghes GJ, Eracleous E, Economides C, Kolnagou A. Advances in iron overload therapies. prospects for effective use of deferiprone (L1), deferoxamine, the new experimental chelators ICL670, GT56-252, L1NA11 and their combinations. Curr Med Chem 2005;12:2663-81.
24. Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer 2013;13:342-55.
25. Chong TW, Horwitz LD, Moore JW, Sowter HM, Harris AL. A mycobacterial iron chelator, desferri-exochelin, induces hypoxia-inducible factors 1 and 2, NIP3, and vascular endothelial growth factor in cancer cell lines. Cancer Res 2002;62:6924-7.
26. Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 2002;13:572-84.
27. Morel I,Lescoat G, Cogrel P, Sergent O, Pasdeloup N, Brissot P, et al. Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem Pharmacol 1993;45:13-9.
28. Jiao Y, Wilkinson J, Di X, Wang W, Hatcher H, Kock ND. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 2009;113:462-9.
29. Farombi EO, Nwaokeafor IA. Anti-oxidant mechanisms of kolaviron: studies on serum lipoprotein oxidation, metal chelation and oxidative membrane damage in rats. Clin Exp Pharmacol Physiol 2005;32:667-74.
30. Perez CA, Wei Y, Guo M. Iron-binding and anti-fenton properties of baicalein and baicalin. J Inorg Biochem 2009;103:326-32.
31. Zhang Z, Wei T, Hou J, Li G, Yu S, Xin W. Iron-induced oxidative damage and apoptosis in cerebellar granule cells: attenuation by tetramethylpyrazine and ferulic acid. Eur J Pharmacol 2003;467:41-7.
32. Bandara BM, Hewage CM, Karunaratne V, Adikaram NK. Methyl ester of para-coumaric acid: antifungal principle of the rhizome of Costus speciosus. Planta Med 1988;54:477-8.
33. Hatcher HC, Singh RN, Torti FM, Torti SV. Synthetic and natural iron chelators: therapeutic potential and clinical use. Future Med Chem 2009;1:1643-70.
34. Mirzaei A, Khatami R. Antioxidant and iron chelating activity of Coriander sativum and petroselinum crispum. Bull Environ Pharmacol Life Sci 2013;2:27-31.
35. Aznar A, Chen NW, Rigault M, Riache N, Joseph D, DesmaÃ«le D, et al. Scavenging iron: a novel mechanism of plant immunity activation by microbial siderophores. Plant Physiol 2014;164:2167-83.
36. Aznar A, Dellagi A. New insights into the role of siderophores as triggers of plant immunity: what can we learn from animals? J Exp Bot 2015;66:3001-10.
37. Kitsati N, Fokas D, Ouzouni MD, Mantzaris MD, Barbouti A, Galaris D. Lipophilic caffeic acid derivatives protect cells against H2O2-Induced DNA damage by chelating intracellular labile iron. J Agric Food Chem 2012;60:7873-9.
38. Karunaratne V, Bombuwala K, Kathirgamanathar S, Thadhani VM. Lichens: A chemically important biota. J Natl Sci Found 2005;33:169-86.
39. Kathirgamanathar S, Ratnasooriya WD, Baekstrom P, Andersen RJ, Karunaratne V. Chemistry and bioactivity of Physciaceae lichens Pyxine consocians and Heterodermia leucomelos. Pharm Biol 2006;44:217-20.
40. Kekuda TRP, Vinayaka KS, Swathi D, Suchitha Y, Venugopal TM, Mallikarjun N. Mineral composition, total phenol content and antioxidant activity of a macrolichen Everniastrum cirrhatum (Fr.) Hale (Parmeliaceae). E J Chem 2011;8:1886-94.
41. Sahib K, Kularatne NS, Kumar S, Karunaratne V. Effect of+usnic acid on the shothole borer Xyleborus fornicatus Eichh of tea. J Natl Sci Found 2009;36:335-6.
42. Kathirgamanathar S, Williams DE, Andersen RJ, Bombuwela K, De Silva D, Karunaratne V. Beta-orcinol depsidones from the lichen Usnea sp. from Sri Lanka. Nat Prod Res 2005;19:695-701.
43. Thadhani VM, Choudhary MI, Ali S, Omar I, Siddique H, Karunaratne V. Antioxidant activity of some lichen metabolites. Nat Prod Res 2011;25:1827-37.