The Fenton Activity of Iron(III) in the Presence of Deferiprone

Devanur, Lakshmi D.; Neubert, Hendrik; Hider, Robert C.

doi:10.1002/jps.21039

Cited by 36 publications

(34 citation statements)

References 34 publications

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“…Our current model (Fig. 8), one that is supported by the data presented here, as well as the published work of others, is that a sublethal concentration of DFP complexes with ferric iron in the medium (DFP-Fe 3ϩ ), which is the preferred form of iron that binds DFP (54). We believe that the presence of antibiotics may lead to disruption of the bacterial membrane, which then facilitates DFPFe 3ϩ entry into the cytoplasm.…”

Section: Figsupporting

confidence: 88%

Escherichia coli Free Radical-Based Killing Mechanism Driven by a Unique Combination of Iron Restriction and Certain Antibiotics

Gao

Maresso

2015

J Bacteriol

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Bacterial resistance to antibiotics is precipitating a medical crisis, and new antibacterial strategies are being sought. Hypothesizing that a growth-restricting strategy could be used to enhance the efficacy of antibiotics, we determined the effect of FDA-approved iron chelators and various antibiotic combinations on invasive and multidrug-resistant extraintestinal pathogenic Escherichia coli (ExPEC), the Gram-negative bacterium most frequently isolated from the bloodstreams of hospitalized patients. We report that certain antibiotics used at sublethal concentrations display enhanced growth inhibition and/or killing when combined with the iron chelator deferiprone (DFP). Inductively coupled plasma optical emission spectrometry reveals abnormally high levels of cell-associated iron under these conditions, a response that correlates with an iron starvation response and supraphysiologic levels of reactive oxygen species (ROS). The high ROS level is reversed upon the addition of antioxidants, which restores bacterial growth, suggesting that the cells are inhibited or killed by excessive free radicals. A model is proposed in which peptidoglycan-targeting antibiotics facilitate the entry of lethal levels of iron-complexed DFP into the bacterial cytoplasm, a process that drives the generation of ROS. This new finding suggests that, in addition to restriction of access to iron as a general growth-restricting strategy, targeting of cellular pathways or networks that selectively disrupt normal iron homeostasis can have potent bactericidal outcomes. IMPORTANCEThe prospect that common bacteria will become resistant to all antibiotics is challenging the medical community. In addition to the development of next-generation antibiotics, new bacterial targets that display cytotoxic properties when altered need to be identified. Data presented here demonstrate that combining subinhibitory levels of both iron chelators and certain antibiotics kills pathogenic Escherichia coli. The mechanism of this effect is the production of supraphysiologic levels of reactive oxygen species, likely powered by the excessive import of iron. These findings were consistent for both clinically relevant and no longer clinically used antibiotics and may extend to Staphylococcus aureus as well.A ntibiotics are compounds that inhibit or kill bacteria and may have saved more lives than any other medical intervention, aside from vaccination (1). However, the development of strains resistant to antibiotics is precipitating a medical crisis. It is estimated that each year in the United States there are 900,000 cases of antibiotic-resistant infections, with an estimated cost of over 20 billion U.S. dollars (2). Several factors contribute to resistance, including the over-and misuse of these drugs (which generates evolutionary pressure that selects for resistant strains), horizontal gene transfer (which allows elements that confer resistance to be transferred among species or genera), and the high level of genetic diversity generated from de novo muta...

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Section: Figsupporting

confidence: 88%

Escherichia coli Free Radical-Based Killing Mechanism Driven by a Unique Combination of Iron Restriction and Certain Antibiotics

Gao

Maresso

2015

J Bacteriol

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“…We surmised that under physiologic conditions iron transfer to aTf is likely to occur (1) spontaneously, as the pFe value of Fe(III) for transferrin is 3 orders of magnitude higher than for DFP 41 (Table 1), and (2) directly as Fe(III), because the thermodynamically favored DFP-Fe complexes are (DFP) 2 -Fe(III) and (DFP) 3 -Fe(III). 10,25,42 In vitro studies based on an indirect analytical method 11 corroborated earlier observations that a single oral dose of 3 g DFP raised within 6 hours the transferrin saturation (determined by urea-gel electrophoresis) of a healthy individual from a normal level of 20% to 80%. 12 In this work we provided direct demonstration of iron transfer from DFP-Fe to aTf at physiologic concentrations ( Figure 5).…”

Section: Discussionmentioning

confidence: 57%

“…This tendency is present in chelators with relatively low redox potentials, such as those based on amine-and carboxylliganding groups but not with the bidentate 3:1 complexing hydroxypyridone DFP. 20,21,44,45 However, speciation studies 10 and recent examination of ROS production 42 indicated that complete abolition of labile iron by DFP is attained only at DFP:Fe(III) ratios close to 5:1. Whether DFP levels reached therapeutically are consistently high enough to avoid formation of substoichiometric redox-active complexes is difficult to predict.…”

Section: Discussionmentioning

confidence: 99%

Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications

Sohn

Breuer

Münnich

et al. 2008

Blood

160

149

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Various pathologies are characterized by the accumulation of toxic iron in cell compartments. In anemia of chronic disease, iron is withheld by macrophages, leaving extracellular fluids iron-depleted. In Friedreich ataxia, iron levels rise in the mitochondria of excitable cells but decrease in the cytosol. We explored the possibility of using deferiprone, a membrane-permeant iron chelator in clinical use, to capture labile iron accumulated in specific organelles of cardiomyocytes and macrophages and convey it to other locations for physiologic reuse. Deferiprone's capacity for shuttling iron between cellular organelles was assessed with organelle-targeted fluorescent iron sensors in conjunction with time-lapse fluorescence microscopy imaging. Deferiprone facilitated transfer of iron from extracellular media into nuclei and mitochondria, from nuclei to mitochondria, from endosomes to nuclei, and from intracellular compartments to extracellular apotransferrin. Furthermore, it mobilized iron from iron-loaded cells and donated it to preerythroid cells for hemoglobin synthesis, both in the presence and in the absence of transferrin. These unique properties of deferiprone underlie mechanistically its capacity to alleviate iron accumulation in dentate nuclei of Friedreich ataxia patients and to donate tissuechelated iron to plasma transferrin in thalassemia intermedia patients. Deferiprone's shuttling properties could be exploited clinically for treating diseases involving regional iron accumulation. IntroductionThe pathologic effects of iron accumulation in tissue are recognized in diseases of systemic iron overload, in which the liver, heart, and endocrine glands are the principal affected organs. 1 At the cellular level, labile iron begins to rise once the intracellular capacity for iron storage is surpassed, leading to catalytic formation of reactive oxygen species (ROS) that ultimately overwhelm the cellular antioxidant defense mechanisms and lead to cell damage. 2 In recent years, several pathologies have been shown to be associated with specific defects in cellular iron metabolism that do not give rise to conspicuous systemic iron overload. 3 In the neuromuscular disorder Friedreich ataxia, the deficiency of the iron-chaperone protein frataxin is thought to lead to mitochondrial iron accumulation due to improper processing of iron for heme and iron-sulfur-cluster formation. 4 In the group of neuromuscular disorders termed NBIA (neurodegeneration with brain iron accumulation), a deficiency in pantothenate kinase (PKAN-2), a key enzyme in coenzyme A synthesis, 5 leads to iron deposition and ensuing brain damage by still-unresolved mechanisms. 6 In hereditary X-linked sideroblastic anemia, impaired heme synthesis causes mitochondrial iron accumulation and siderosis in erythroid cells. 3 However, an extreme example of systemic misdistribution of iron is encountered in anemia of chronic disease (ACD), where iron accumulates in reticuloendothelial cells responsible for recycling aged erythrocytes, presumably due to d...

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“…The Fe 3+ complexes can shows several labile positions to be substituted by H 2 O 2 and, if the ligand is redox active, reduce Fe 3+ (65,66) . Devanur et al (67) , synthetized a deferiprone biscomplex. This compound have two free coordination sites for water that can be replaced by H 2 O 2 producing a peroxo-complex and releasing •OH.…”

Section: Ligands Effects On Fenton Reactionmentioning

confidence: 99%

Fenton Reaction Driven by Iron Ligands

Salgado

Melín

Contreras

et al. 2013

J. Chil. Chem. Soc.

102

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One of the most important sources of reactive oxygen species (ROS) in biological systems is the Fenton reaction. In this, the Fe 2+ or Fe 3+ reacts with H 2 O 2 to produce ROS as the hydroxyl radical (•OH), superoxide radical (O 2 •-) and singlet oxygen ( 1 O 2 ). The main ROS, responsible for the high oxidizing power of the Fenton reaction, is not clear. Some authors claim that the principal reactive species is •OH, while others propose a ferryl specie (Fe 4+ or [FeO] 2+ ) (1,2) . Recently, have been proposed that the kind of reaction species produced depends mainly of pH and the iron composition of the coordination sphere. This is highlighted for Fe 3+ , because in mono and (some) bis-complexes Fe 3+ is reduced to Fe 2+ and there are some positions occupied by water or hydroxide ligands, readily to be exchanged by H 2 O 2 . On the other hand, in tris-complexes there are not any positions occupied by water or hydroxide, avoiding the formation of peroxo-complexes, necessary for Fenton or Fenton like reaction.The 1,2-dihydroxybenzenes (DHBs) have been described as modulators of Fenton reaction. The DHBs driven Fenton reaction have been used for environmental applications as an advanced oxidation process. Furthermore, these systems participate in different biological process, as the wood biodegradation by fungi and oxidative stress in neurodegenerative diseases.In this review, the effect of 1,2-dihydroxybenzenes on the activated species production by the Fenton and Fenton like reaction will be discussed and its participation in different systems.

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The Fenton Activity of Iron(III) in the Presence of Deferiprone

Cited by 36 publications

References 34 publications

Escherichia coli Free Radical-Based Killing Mechanism Driven by a Unique Combination of Iron Restriction and Certain Antibiotics

Escherichia coli Free Radical-Based Killing Mechanism Driven by a Unique Combination of Iron Restriction and Certain Antibiotics

Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications

Fenton Reaction Driven by Iron Ligands

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