Iron Uptake Research Articles

Priming effects of nZVI on carbon sequestration and iron uptake are positively mediated by AM fungus in semiarid agricultural soils

We investigated the priming effect of nanoscale zero-valent iron (nZVI) on carbon sink and iron uptake, and the possible mediation by AMF (arbuscular mycorrhizal fungi, Funneliformis mosseae) in semiarid agricultural soils. Maize seed dressings comprised of three nZVI concentrations of 0, 1, 2 g·kg−1 and was tested with and without AMF inoculation under high and low soil moistures, respectively. The ICP-OES observations indicated that both low dose of nZVI (1 g·kg−1) and high dose of nZVI (2 g·kg−1) significantly increased the iron concentrations in roots (L: 54.5–109.8 %; H: 119.1–245.4 %) and shoots (L: 40.8–78.9 %; H: 81.1–99.4 %). Importantly, the absorption and translocation rate of iron were substantially improved by AMF inoculation under the low-dose nZVI. Yet, the excess nanoparticles as a stress were efficiently relieved by rhizosphere hyphae, and the iron concentration in leaves and stems can maintain as high as about 300 mg·kg−1 while the iron translocation efficiency was reduced. Moreover, next-generation sequencing confirmed that appropriate amount of nZVI clearly improved the rhizosphere colonization of Funneliformis mosseae (p < 0.001) and the development of soil fungal community. Soil observations further showed that the hyphae development and GRSP (glomalin-related soil protein) secretion were significantly promoted (p < 0.05), with the increased R0.25 (< 0.25 mm) by 35.97–41.16 %. As a return, AMF and host plant turned to input more organic matter into soils for microbial growth and Fe uptake, and such interactions became more pronounced under drought stress. In contrast, high dose of nZVI (2 g·kg−1) tended to agglomerate on the surface of hyphae and spores, causing severe deformation and inactivation of AMF symbionts. Therefore, the priming effects of nZVI on carbon sequestration and Fe uptake in agricultural soils were positively mediated by AMF via the feedback loop of the plant-soil-microbe system for enhanced adaptation to global climate change.

A dynamic compartment model for xylem loading and long-distance transport of iron explains the effect of kanamycin on metal uptake in Arabidopsis.

Arabidopsis plants exposed to the antibiotic kanamycin (Kan) display altered metal homeostasis. Further, mutation of the WBC19 gene leads to increased sensitivity to kanamycin and changes in iron (Fe) and zinc (Zn) uptake. Here we propose a model that explain this surprising relationship between metal uptake and exposure to Kan. We first use knowledge about the metal uptake phenomenon to devise a transport and interaction diagram on which we base the construction of a dynamic compartment model. The model has three pathways for loading Fe and its chelators into the xylem. One pathway, involving an unknown transporter, loads Fe as a chelate with citrate (Ci) into the xylem. This transport step can be significantly inhibited by Kan. In parallel, FRD3 transports Ci into the xylem where it can chelate with free Fe. A third critical pathway involves WBC19, which transports metal-nicotianamine (NA), mainly as Fe-NA chelate, and possibly NA itself. To permit quantitative exploration and analysis, we use experimental time series data to parameterize this explanatory and predictive model. Its numerical analysis allows us to predict responses by a double mutant and explain the observed differences between data from wildtype, mutants and Kan inhibition experiments. Importantly, the model provides novel insights into metal homeostasis by permitting the reverse-engineering of mechanistic strategies with which the plant counteracts the effects of mutations and of the inhibition of iron transport by kanamycin.

Optical Monitoring of In Situ Iron Loading into Single, Native Ferritin Proteins.

Ferritin is a protein that stores and releases iron to prevent diseases associated with iron dysregulation in plants, animals, and bacteria. The conversion between iron-loaded holo-ferritin and empty apo-ferritin is an important process for iron regulation. To date, studies of ferritin have used either ensemble measurements to quantify the characteristics of a large number of proteins or single-molecule approaches to interrogate labeled or modified proteins. Here we demonstrate the first real-time study of the dynamics of iron ion loading and biomineralization within a single, unlabeled ferritin protein. Using optical nanotweezers, we trapped single apo- and holo-ferritins indefinitely, distinguished one from the other, and monitored their structural dynamics in real time. The study presented here deepens the understanding of the iron uptake mechanism of ferritin proteins, which may lead to new therapeutics for iron-related diseases.

Effect of calcium and trace metals (Cd, Cu, Mn, Ni, Zn) on root iron uptake in relation to chemical properties of the root-excreted ligands.

Interferences of major cations (Ca2+, Mg2+) and trace metals (TM, i.e. Cd2+, Cu2+, Mn2+, Ni2+ and Zn2+) in root Fe uptakewere evaluated. Root Fe uptake was modelled including the reactions of the root exuded ligand with the soil major and trace cations. Fe uptake was simulated with different ligands representing various affinities for the cations, the latter varying in concentration. The stability constant of Fe complexes (KFeL) does not influence Fe uptake, contrarily to the ligand parameters for Fe-hydroxide dissolution. Fe uptake decreases when KCaL or Ca2+ in solution increases. Presence of TM has nearly no influence on Fe uptake when the TM complexes have low stability constants (KML), as in the case of oxalate and citrate complexes. When ligands have high KML, like EDTA, DFO-B or mugineic acid (MA), TM reduces Fe uptake by 51-55%, and much more in the case of TM contamination. Exudation of Fe ligands with low KML has no negative effect on TM uptake, which can increase if the dissociation rate is high, as for Cu complexes. Ligands with high KML (EDTA, DFO-B, MA) greatly reduce TM uptake, only if their hydrated cations can be absorbed. Calcium does not significantly reduce Fe uptake when Ca-complexes have KCaL < 104. Consequently, ligands like oxalate or MA should be efficient in most soils. TM should perturbate Fe uptake mediated by ligands with high KML such as MA, but not oxalate. Plants exuding phytosiderophores should also absorb TM complexes to avoid micronutrient deficiencies.

Brain iron acquisition: An overview of homeostatic regulation and disease dysregulation.

Brain iron homeostasis is crucial for neurological health, with pathological fluctuations in brain iron levels associated with a variety of neurological disorders. Low levels are connected to cognitive impairment and restless legs syndrome, while high levels are connected to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Given the detrimental effects unrestricted iron can have, regulated entry into the brain via transferrin and H-ferritin is critical. Endothelial cells of the blood-brain barrier are the site of iron transport regulation. The movement of iron through endothelial cells into the brain can be divided into three distinct processes: uptake, transcytosis, and release. Each process possesses external and internal influences on the regulation at each stage. This review discusses the mechanisms of iron uptake, transcytosis, and release at the blood-brain barrier, as well as the elements that contribute to regulation. Additionally, we explore the dysregulation of brain iron in Alzheimer's disease, Parkinson's disease, and restless legs syndrome.

Pseudomonas aeruginosa responds to altered membrane phospholipid composition by adjusting the production of two-component systems, proteases and iron uptake proteins

Membrane protein and phospholipid (PL) composition changes in response to environmental cues and during infections. To achieve these, bacteria use adaptation mechanisms involving covalent modification and remodelling of the acyl chain length of PLs. However, little is known about bacterial pathways regulated by PLs. Here, we investigated proteomic changes in the biofilm of P. aeruginosa phospholipase mutant (∆plaF) with altered membrane PL composition. The results revealed profound alterations in the abundance of many biofilm-related two-component systems (TCSs), including accumulation of PprAB, a key regulator of the transition to biofilm. Furthermore, a unique phosphorylation pattern of transcriptional regulators, transporters and metabolic enzymes, as well as differential production of several proteases, in ∆plaF, indicate that PlaF-mediated virulence adaptation involves complex transcriptional and posttranscriptional response. Moreover, proteomics and biochemical assays revealed the depletion of pyoverdine-mediated iron uptake pathway proteins in ∆plaF, while proteins from alternative iron-uptake systems were accumulated. These suggest that PlaF may function as a switch between different iron-acquisition pathways. The observation that PL-acyl chain modifying and PL synthesis enzymes were overproduced in ∆plaF reveals the interconnection of degradation, synthesis and modification of PLs for proper membrane homeostasis. Although the precise mechanism by which PlaF simultaneously affects multiple pathways remains to be elucidated, we suggest that alteration of PL composition in ∆plaF plays a role for the global adaptive response in P. aeruginosa mediated by TCSs and proteases. Our study revealed the global regulation of virulence and biofilm by PlaF and suggests that targeting this enzyme may have therapeutic potential.

Duodenal macrophages control dietary iron absorption via local degradation of transferrin

AbstractIron is an essential cellular metal that is important for many physiological functions including erythropoiesis and host defense. It is absorbed from the diet in the duodenum and loaded onto transferrin (Tf), the main iron transport protein. Inefficient dietary iron uptake promotes many diseases, but mechanisms regulating iron absorption remain poorly understood. By assessing mice that harbor a macrophage-specific deletion of the tuberous sclerosis complex 2 (Tsc2), a negative regulator of mechanistic target of rapamycin complex 1 (mTORC1), we found that these mice possessed various defects in iron metabolism, including defective steady-state erythropoiesis and a reduced saturation of Tf with iron. This iron deficiency phenotype was associated with an iron import block from the duodenal epithelial cells into the circulation. Activation of mTORC1 in villous duodenal CD68+ macrophages induced serine protease expression and promoted local degradation of Tf, whereas the depletion of macrophages in mice increased Tf levels. Inhibition of mTORC1 with everolimus or serine protease activity with nafamostat restored Tf levels and Tf saturation in the Tsc2-deficient mice. Physiologically, Tf levels were regulated in the duodenum during the prandial process and Citrobacter rodentium infection. These data suggest that duodenal macrophages determine iron transfer to the circulation by controlling Tf availability in the lamina propria villi.

Distinct drivers of two size fractions of operationally dissolved iron in a temperate river

AbstractRiverine dissolved iron (Fe) affects water color, nutrients, and marine carbon cycling. Fe size and coupling with dissolved organic matter (DOM), in part, modulates the biogeochemical roles of riverine Fe. We used size fractionation to operationally define dissolved Fe (&lt; 0.22 μm) into soluble (&lt; 0.02 μm) and colloidal (0.02–0.22 μm) fractions in order to characterize the downstream drivers, concentrations, and fluxes of Fe across season and hydrologic regime at the freshwater Connecticut River mainstem, which we sampled bi‐weekly for 2 yrs. Drivers of colloidal and soluble Fe concentrations were markedly different. The response of colloidal Fe concentration to changes in discharge was modulated by water temperature; colloidal Fe decreased with increasing discharge at temperatures &lt; 10.5°C, but increased with increasing discharge at temperatures &gt; 10.5°C. Conversely, soluble Fe concentrations were only positively correlated to discharge at high temperatures (&gt; 20°C). Soluble Fe was strongly positively correlated to a humic‐like DOM fluorescence component, suggesting coupling with DOM subsets, potentially through complexation. While average colloidal Fe fluxes varied twofold seasonally, soluble Fe fluxes varied ninefold; therefore, soluble Fe variability was more important to the overall dissolved Fe variability than colloidal Fe, despite lower concentrations. Seasonal Fe fluxes were decoupled from discharge: dissolved and soluble Fe fluxes were greatest in the fall, whereas discharge was greatest in the spring. Fluxes of soluble Fe, which may be more bioavailable and more likely to be exported to the ocean, were lowest in the summer when downstream biological demand is high, having implications for primary productivity and iron uptake.

Removal of copper and iron from ethanolic solutions by an anion exchange resin and its implication to rare-earth magnet recycling

In the recycling of end-of-life rare-earth magnets, the recovery of non-rare earth constituents is often neglected. In the present study, strong cation and anion exchange resins were tested batchwise for the recovery of the non-rare-earth constituents of permanent magnets (copper, cobalt, manganese, nickel and iron) from synthetic aqueous and ethanolic solutions. The cation exchange resin recovered most of metal ions from aqueous and ethanolic feeds, whereas the anion exchange resin could selectively recover copper and iron from ethanolic feeds. The highest uptake of iron and copper was found for 80 vol% and 95 vol% multi-element ethanolic feeds, respectively. A similar trend in selectivity of the anion resin was observed in breakthrough curve studies. Batch experiments, UV–Vis, FT-IR and XPS studies were performed to elucidate the ion exchange mechanism. The studies indicate that the formation of chloro complexes of copper and their exchange by the (hydrogen) sulfate counter ions of the resin have an important role in the selective uptake of copper from the 95 vol% ethanolic feed. Iron(II) was largely oxidized to iron(III) in ethanolic solutions and was expected to be recovered by the resin in the form of iron(II) and iron(III) complexes. The moisture content of the resin did not have a significant role on the selectivity for copper and iron.

Abstract 1381: Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells

Abstract Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Ferroptosis is an iron dependent non-apoptotic cell death due to catastrophic accumulation of lipid peroxidation. While the mechanism that determines ferroptosis sensitivity has been extensively investigated in attached cells, how cells respond to ferroptosis under ECM detachment is largely unknown. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. While alterations in membrane lipid content are observed during ECM-detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM-detachment due to changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of iron storage proteins sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy towards ECM-detached cells. Citation Format: Jianping He, Abigail M. Abikoye, Brett P. McLaughlin, Ryan S. Middleton, Ryan Sheldon, Russell G. Jones, Zachary T. Schafer. Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1381.

Transcriptomic profiling of the yeast Komagataella phaffii in response to environmental alkalinization

BackgroundAdaptation to alkalinization of the medium in fungi involves an extensive remodeling of gene expression. Komagataella phaffii is an ascomycetous yeast that has become an organism widely used for heterologous protein expression. We explore here the transcriptional impact of moderate alkalinization in this yeast, in search of suitable novel promoters able to drive transcription in response to the pH signal.ResultsIn spite of a minor effect on growth, shifting the cultures from pH 5.5 to 8.0 or 8.2 provokes significant changes in the mRNA levels of over 700 genes. Functional categories such as arginine and methionine biosynthesis, non-reductive iron uptake and phosphate metabolism are enriched in induced genes, whereas many genes encoding iron-sulfur proteins or members of the respirasome were repressed. We also show that alkalinization is accompanied by oxidative stress and we propose this circumstance as a common trigger of a subset of the observed changes. PHO89, encoding a Na+/Pi cotransporter, appears among the most potently induced genes by high pH. We demonstrate that this response is mainly based on two calcineurin-dependent response elements located in its promoter, thus indicating that alkalinization triggers a calcium-mediated signal in K. phaffii.ConclusionsThis work defines in K. phaffii a subset of genes and diverse cellular pathways that are altered in response to moderate alkalinization of the medium, thus setting the basis for developing novel pH-controlled systems for heterologous protein expression in this fungus.

First report on biological iron uptake in the Antarctic sea-ice environment

Melting sea ice is a seasonal source of iron (Fe) to the Southern Ocean (SO), where Fe levels in surface waters are otherwise generally too low to support phytoplankton growth. However, the effectiveness of sea-ice Fe fertilization in stimulating SO primary production is unknown since no data exist on Fe uptake by microorganisms in the sea-ice environment. This study reports a unique dataset on Fe uptake rates, Fe-to-carbon (C) uptake ratio (Fe uptake normalized to C uptake) and Fe:C uptake rate (Fe uptake normalized to biomass) by in situ microbial communities inhabiting sea ice and the underlying seawater. Radioisotopes 55Fe and 14C were used in short-term uptake experiments during the 32-day Ice Station POLarstern (ISPOL) time series to evaluate the contributions of small (0.8–10 µm) and large (> 10 µm) microbes to Fe uptake. Overall, results show that over 90% of Fe was bound to the outside of the cells. Intracellular Fe (Feintra) uptake rates reached up to 68, 194, and 203 pmol Fe L−1d− 1 in under-ice seawater, bottom ice, and top ice, respectively. Inorganic carbon uptake ranged between 0.03 and 3.2 µmol C L−1 d−1, with the lowest rate observed in under-ice seawater. Importantly, between the start and end of ISPOL, we observed a 30-fold increase in Feintra normalized to carbon biomass in bottom sea ice. This trend was likely due to changes in the microbial community from a dominance of large diatoms at the start of the survey to small diatoms later in the season. As the Antarctic icescape and associated ecosystems are changing, this dataset will help inform the parameterisation of sea-ice biogeochemical and ecological models in ice-covered regions.

Genomic characterization and identification of virulence-related genes in Vibrio nigripulchritudo isolated from white leg shrimp Penaeus vannamei.

Vibrio nigripulchritudo causes vibriosis in penaeid shrimps. Here, we used Illumina and Nanopore sequencing technologies to sequence the genomes of three of its strains (TUMSAT-V. nig1, TUMSAT-V. nig2, and TUMSAT-V. nig3) to explore opportunities for disease management. Putative virulence factors and mobile genetic elements were detected while evaluating the phylogenetic relationship of each isolated strain. The genomes consisted of two circular chromosomes (I and II) plus one or two plasmids. The size of chromosome I ranged from 4.02 to 4.07 Mb with an average GC content of 46%, while the number of predicted CDSs ranged from 3563 to 3644. The size of chromosome II ranged from 2.16 to 2.18 Mb, with an average GC content of 45.5%, and the number of predicted CDSs ranged from 1970 to 1987. Numerous virulence genes were identified related to adherence, antiphagocytosis, chemotaxis, motility, iron uptake, quorum sensing, secretion systems, and toxins in all three genomes. Higher numbers of prophages and genomic islands found in TUMSAT-V. nig1 suggest that the strain has experienced numerous horizontal gene transfer events. The presence of antimicrobial resistance genes suggests that the strains have multidrug resistance. Comparative genomic analysis showed that all three strains belonged to the same clade.

Transferrin receptor is necessary for proper oligodendrocyte iron homeostasis and development.

To test the hypothesis that the transferrin (Tf) cycle has unique importance for oligodendrocyte development and function, we disrupted the expression of the Tf receptor (Tfr) gene in oligodendrocyte progenitor cells (OPCs) on mice of either sex using the Cre/lox system. This ablation results in the elimination of iron incorporation via the Tf cycle but leaves other Tf functions intact. Mice lacking Tfr, specifically in NG2 or Sox10-positive OPCs, developed a hypomyelination phenotype. Both OPCs differentiation and myelination were affected, and Tfr deletion resulted in impaired OPC iron absorption. Specifically, the brains of Tfr cKO animals presented a reduction in the quantity of myelinated axons, as well as fewer mature oligodendrocytes. In contrast, the ablation of Tfr in adult mice affected neither mature oligodendrocytes nor myelin synthesis. RNA-seq analysis performed in Tfr cKO OPCs revealed misregulated genes involved in OPC maturation, myelination, and mitochondrial activity. Tfr deletion in cortical OPCs also disrupted the activity of the mTORC1 signaling pathway, epigenetic mechanisms critical for gene transcription and the expression of structural mitochondrial genes. RNA-seq studies were additionally conducted in OPCs in which iron storage was disrupted by deleting the ferritin heavy chain. These OPCs display abnormal regulation of genes associated with iron transport, antioxidant activity, and mitochondrial activity. Thus, our results indicate that the Tf cycle is central for iron homeostasis in OPCs during postnatal development and suggest that both iron uptake via Tfr and iron storage in ferritin are critical for energy production, mitochondrial activity, and maturation of postnatal OPCs.SIGNIFICANCE STATEMENT:By knocking-out transferrin receptor (Tfr) specifically in oligodendrocyte progenitor cells (OPCs) we have established that iron incorporation via the Tf cycle is key for OPC iron homeostasis and for the normal function of these cells during the postnatal development of the CNS. Moreover, RNA-seq analysis indicated that both Tfr iron uptake and ferritin iron storage are critical for proper OPC mitochondrial activity, energy production, and maturation.

Grf10 regulates the response to copper, iron, and phosphate in Candida albicans.

The pathogenic yeast, Candida albicans, and other microbes must be able to handle drastic changes in nutrient availability within the human host. Copper, iron, and phosphate are essential micronutrients for microbes that are sequestered by the human host as nutritional immunity; yet high copper levels are employed by macrophages to induce toxic oxidative stress. Grf10 is a transcription factor important for regulating genes involved in morphogenesis (filamentation, chlamydospore formation) and metabolism (adenylate biosynthesis, 1-carbon metabolism). The grf10Δ mutant exhibited resistance to excess copper in a gene dosage-dependent manner but grew the same as the wild type in response to other metals (calcium, cobalt, iron, manganese, and zinc). Point mutations in the conserved residues D302 and E305, within a protein interaction region, conferred resistance to high copper and induced hyphal formation similar to strains with the null allele. The grf10Δ mutant misregulated genes involved with copper, iron, and phosphate uptake in YPD medium and mounted a normal transcriptional response to high copper. The mutant accumulated lower levels of magnesium and phosphorus, suggesting that copper resistance is linked to phosphate metabolism. Our results highlight new roles for Grf10 in copper and phosphate homeostasis in C. albicans and underscore the fundamental role of Grf10 in connecting these with cell survival.

The Imbalance of p53-Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin-Challenged Cardiomyocytes.

Doxorubicin (DOX)-induced cardiotoxicity (DoIC) is a major side effect for cancer patients. Recently, ferroptosis, triggered by iron overload, is demonstrated to play a role in DoIC. How iron homeostasis is dysregulated in DoIC remains to be elucidated. Here, the authors demonstrate that DOX challenge exhibits reduced contractile function and induction of ferroptosis-related phenotype in cardiomyocytes, evidenced by iron overload, lipid peroxide accumulation, and mitochondrial dysfunction. Compared to Ferric ammonium citrate (FAC) induced secondary iron overload, DOX-challenged cardiomyocytes show a dysfunction of iron homeostasis, with decreased cytoplasmic and mitochondrial iron-sulfur (FeS) cluster-mediated aconitase activity and abnormal expression of iron homeostasis-related proteins. Mechanistically, mass spectrometry analysis identified DOX-treatment induces p53-dependent degradation of Parkinsonism associated deglycase (Park7) which results in iron homeostasis dysregulation. Park7 counteracts iron overload by regulating iron regulatory protein family transcription while blocking mitochondrial iron uptake. Knockout of p53 or overexpression of Park7 in cardiomyocytes remarkably restores the activity of FeS cluster and iron homeostasis, inhibits ferroptosis, and rescues cardiac function in DOX treated animals. These results demonstrate that the iron homeostasis plays a key role in DoIC ferroptosis. Targeting of the newly identified p53-Park7 signaling axis may provide a new approach to prevent DoIC.

Cross-Talk between Iron Deficiency Response and Defense Establishment in Plants

Plants are at risk of attack by various pathogenic organisms. During pathogenesis, microorganisms produce molecules with conserved structures that are recognized by plants that then initiate a defense response. Plants also experience iron deficiency. To address problems caused by iron deficiency, plants use two strategies focused on iron absorption from the rhizosphere. Strategy I is based on rhizosphere acidification and iron reduction, whereas Strategy II is based on iron chelation. Pathogenic defense and iron uptake are not isolated phenomena: the antimicrobial phenols are produced by the plant during defense, chelate and solubilize iron; therefore, the production and secretion of these molecules also increase in response to iron deficiency. In contrast, phytohormone jasmonic acid and salicylic acid that induce pathogen-resistant genes also modulate the expression of genes related to iron uptake. Iron deficiency also induces the expression of defense-related genes. Therefore, in the present review, we address the cross-talk that exists between the defense mechanisms of both Systemic Resistance and Systemic Acquired Resistance pathways and the response to iron deficiency in plants, with particular emphasis on the regulation genetic expression.

Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we conducted a systematic literature search in PubMed, Web of Science, and Scopus, to collect information on innovative strategies to hinder iron acquisition in bacteria. In detail, we discussed the most interesting targets from iron uptake and metabolism pathways, and examined the main chemical entities that exhibit anti-infective activities by interfering with their function. The mechanism of action of each drug candidate was also reviewed, together with its pharmacodynamic, pharmacokinetic, and toxicological properties. The comprehensive knowledge of such an impactful area of research will hopefully reflect in the discovery of newer antibiotics able to effectively tackle the antimicrobial resistance issue.

Transcriptomic analysis of the effect of deferoxamine exposure on the growth, photosynthetic activity and iron transfer of Microcystis aeruginosa

Deferoxamine (DFB) is a trihydroxamic acid siderophore that chelates with iron (Fe) to form iron-siderophore complexes. The existence of siderophores in nature changes the form of iron and affects the absorption and utilization of iron by organisms. However, the relationship between siderophores and the growth of Cyanobacteria is largely unknown. In this study, the cellular and transcriptomic responses to the addition of DFB were investigated. A high concentration of DFB (12 mg/L) significantly inhibited the growth of Cyanobacteria cells, reduced photosynthetic activity, and induced the production of peroxidase, with the highest inhibition rate of algal growth of 74.82%. These indexes were also affected for the low (3 mg/L) and medium concentration (6 mg/L) groups, but this difference is closely related to the growth stage of Cyanobacteria cells. This may be due to competition between the cell-associated iron-binding part/system and the extracellular Fe (Ⅲ)-DFB ligand. Transcriptome results showed that most of the genes involved in iron uptake and transport were down-regulated, and only the fur gene encoding the iron uptake regulator protein was significantly up-regulated. Most genes related to photosynthesis, glycolysis, and fatty acid metabolism were also down-regulated, while the obvious up-regulation of a few genes may be a complex regulation in response to the down-regulation of most genes. These findings will provide important insights into the effects of siderophores on iron bioavailability in algae.

Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1: Preclinical Efficacy against Iron Overload and Safety Evaluation.

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or β-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors. Dimeric compounds were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary nonheme iron uptake in both rats and pigs yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiologic function of DMT1 in the gut. SIGNIFICANCE STATEMENT: This report introduces methodology to develop potent, gut-restricted inhibitors of divalent metal transporter 1 (DMT1) and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders.