The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter, IrtAB, plays a vital role in the replication and viability of Mycobacterium tuberculosis (Mtb), where its function is to import iron-loaded siderophores. Unusually, it adopts the canonical type IV exporter fold. Herein, we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP, ADP, or ATP analogue (AMP-PNP) at resolutions ranging from 2.8 to 3.5 Å. The structure of IrtAB bound ATP-Mg2+ shows a "head-to-tail" dimer of nucleotide-binding domains (NBDs), a closed amphipathic cavity within the transmembrane domains (TMDs), and a metal ion liganded to three histidine residues of IrtA in the cavity. Cryo-electron microscopy (Cryo-EM) structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with IrtB. Moreover, the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport cycle. This study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.
Siderophores/metabolism* ; Iron/metabolism* ; Mycobacterium tuberculosis/metabolism* ; Cryoelectron Microscopy ; Adenosine Triphosphate/metabolism* ; ATP-Binding Cassette Transporters

Aims: Endophytic bacteria (EB) living inside plant tissues possess different beneficial traits including siderophore production and other plant growth-promoting (PGP) activities. Siderophore-producing EB promote host plant growth by secreting ferrum in iron-deficient conditions. This study screened 19 siderophore producers in vitro, isolated from upland rice roots grown in mountain farms of Tung Village, Nậm Có Commune, Mù Cang Chải District, Yên Bái Province, Vietnam, for PGP traits, including phosphate solubilisation, indole-3-acetic acid (IAA), ammonia, gelatinase, amylase and catalase production. Methodology and results: The bacteria were identified by Matrix assisted Laser Desorption Ionization Time of Flight mass spectrometry (MALDI-TOF MS). All 19 isolates were identified as genera Pseudomonas, Enterobacter, Pantoe, Bacillus, Burkholderia, Staphylococcus, Ralstonia and Cronotacter. The isolates produced catalase and ammonia. The amount of ammonia ranged from 60.74 ± 0.14 to 466.72 ± 0.18 mg/L. Out of the 19 siderophore producers, 17 (89.47%) were able to solubilise phosphate with solubilisation index (PSI) ranging from 1.12 ± 0.07 to 2.14 ± 0.15. The qualitative assays identified 12 isolates (63.15%) positive for IAA production with a tryptophan concentration of 5 mM, whereas 15 (78.94%) and 17 (89.47%) isolates were positive for gelatin and starch hydrolysis, respectively. Especially, 7 isolates were found to be positive for all tested assays in vitro including Pseudomonas rhodesiae (NC2), Enterobacter asburiae (NC50), Pantoea ananatis (NC63), Bacillus cereus (NC64), Burkholderia cenocepacia (NC110), Staphylococcus sciuri (NC112) and Ralstonia pickettii (NC122). Conclusion, significance and impact of study This study serves as crucial findings of multi-trait plant growth-promoting endophytic bacteria isolated from upland rice root in north-western Vietnam. The seven potential isolates positive for all tested assays could be effective PGP bacteria for bio-inoculants.
Oryza--microbiology ; Siderophores ; Plant Growth Regulators ; Vietnam

Iron is an essential trace element for both humans and bacteria. It plays a vital role in life, such as in redox reactions and electron transport. Strict regulatory mechanisms are necessary to maintain iron homeostasis because both excess and insufficient iron are harmful to life. Competition for iron is a war between humans and bacteria. To grow, reproduce, colonize, and successfully cause infection, pathogens have evolved various mechanisms for iron uptake from humans, principally Fe 3+ -siderophore and Fe 2+ -heme transport systems. Humans have many innate immune mechanisms that regulate the distribution of iron and inhibit bacterial iron uptake to help resist bacterial invasion and colonization. Meanwhile, researchers have invented detection test strips and coupled antibiotics with siderophores to create tools that take advantage of this battle for iron, to help eliminate pathogens. In this review, we summarize bacterial and human iron metabolism, competition for iron between humans and bacteria, siderophore sensors, antibiotics coupled with siderophores, and related phenomena. We also discuss how competition for iron can be used for diagnosis and treatment of infection in the future.
Humans ; Siderophores/metabolism* ; Iron/metabolism* ; Bacteria ; Anti-Bacterial Agents/pharmacology* ; Biological Transport

Antimicrobial resistance is one of the critical public health issues in the world. There is an urgent need to develop effective broad-spectrum antibiotics to treat the infection of multi-drug resistant Gram-negative bacilli. Cefiderocol, developed by the Shionogi Inc. in Japan, is a new type of iron carrier cephalosporin antibiotics, which overcomes the drug resistance of Gram-negative bacilli due to the down-regulation of outer membrane pore protein and the up-regulation of efflux pump, and has good stability to serine- and metallo-carbapenemases. This drug has a broad spectrum and strong antibacterial activity against carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. Cefiderocol can be used to treat complex urinary tract infections (including pyelonephritis), hospital-acquired pneumonia, and ventilator-associated pneumonia. By summarizing the chemical structure, antibacterial mechanism, in vitro antibacterial activity, pharmacokinetics, pharmacodynamics, and clinical treatment of cefiderocol, this review shows the application potential of cefiderocol as a new iron carrier cephalosporin in the treatment of multi-drug resistant Gram-negative bacilli infections.
Cephalosporins/therapeutic use* ; Gram-Negative Bacteria ; Microbial Sensitivity Tests ; Siderophores/pharmacology*

Peach brown rot, caused by Monilinia fructicola, is one of the most serious peach diseases. A strain belonging to the Actinomycetales, named Streptomyces blastmyceticus JZB130180, was found to have a strong inhibitory effect on M. fructicola in confrontation culture. Following the inoculation of peaches in vitro, it was revealed that the fermentation broth of S. blastmyceticus JZB130180 had a significant inhibitory effect on disease development by M. fructicola. The fermentation broth of S. blastmyceticus JZB130180 had an EC₅₀ (concentration for 50% of maximal effect) of 38.3 µg/mL against M. fructicola, as determined in an indoor toxicity test. Analysis of the physicochemical properties of the fermentation broth revealed that it was tolerant of acid and alkaline conditions, temperature, and ultraviolet radiation. In addition, chitinase, cellulase, and protease were also found to be secreted by the strain. The results of this study suggest that S. blastmyceticus JZB130180 may be used for the biocontrol of peach brown rot.
Ascomycota/pathogenicity* ; Bacterial Proteins/metabolism* ; Cell Wall/metabolism* ; Cellulase/metabolism* ; Chitinases/metabolism* ; Fermentation ; Fruit/microbiology* ; Pest Control, Biological/methods* ; Phylogeny ; Plant Diseases/prevention & control* ; Prunus persica/microbiology* ; Siderophores/metabolism* ; Streptomyces/physiology*

Background and Objectives: Iron is an essential element that plays a vital role in a wide variety of cellular processes. But when present in excess concentration in organs, it may increase the risk for liver disease, heart failure, and diabetes. Recently, siderophores, which are iron-chelating agents produced by microorganisms, have attracted tremendous attention because of their strong binding and high selectivity to the ferric form of iron. Thus, the use of siderophore in sequestering excess iron in the body as a form of therapy is very attractive. This study determined the effects of commercially available siderophore in sequestering excess iron in organs such as liver, heart, and pancreas under excess iron conditions. Methodology: First, iron-overload was induced by injecting iron dextran (20 mg) into male ICR mice for three consecutive days. The effects of iron to the liver, heart, and pancreas and the possible sequestration by siderophore were determined by scoring histological sections. The liver iron concentration was also assessed by atomic absorption spectroscopy (AAS). Results and Conclusion The study showed that iron-overloaded mice exhibited skin hyperpigmentation and hemosiderosis in liver, heart, and pancreas. Significant changes in the liver include hepatomegaly and development of tumor. Iron-overloaded mice had 2,935% increase in liver iron content compared to the salinetreated mice. However, when iron-overloaded mice were treated with either 100 µg or 200 µg siderophore, there was a 77% and 84% decrease in liver iron content, respectively. Moreover, the treatment of ironoverloaded mice with siderophore prevented the development of hemosiderosis, tumor, and structural changes in the tissues studied. The results showed that siderophore can effectively reduce excess iron and organ damage in iron-overloaded mice and can be potentially employed in chelation therapy of iron-overload diseases. Further studies on the possible mechanisms of siderophore aside from decreasing iron excess and lowering organ dysfunction are recommended.
Siderophores ; Iron Overload ; Iron Chelating Agents ; Hemosiderosis ; Hepatomegaly

OBJECTIVETo explore the efficacy and safety of deferasirox in aplastic anemia (AA)patients with iron overload.

METHODSA single arm, multi- center, prospective, open- label study was conducted to evaluate absolute change in serum ferritin (SF)from baseline to 12 months of deferasirox administration, initially at a dose of 20 mg·kg(-1)·d(-1), and the safety in 64 AA patients with iron overload.

RESULTSAll patients started their deferasirox treatment with a daily dose of 20 mg · kg(-1) ·d(-1). The mean actual dose was (18.6±3.60) mg · kg(-1)·d(-1). The median SF decreased from 4 924 (2 718- 6 765)μg/L at baseline (n=64) to 3 036 (1 474- 5 551)μg/L at 12 months (n=23) with the percentage change from baseline as 38%. A median SF decrease of 651 (126-2 125)μg/L was observed at the end of study in 23 patients who completed 12 months' treatment, the median SF level decreased by 1 167(580-4 806)μg/L [5 271(3 420-8 278)μg/L at baseline; 3 036(1 474-5 551)μg/L after 12 months' treatment; the percentage change from baseline as 42% ] after 12 months of deferasirox treatment. The most common adverse events (AEs) were increased serum creatinine levels (40.98%), gastrointestinal discomfort (40.98%), elevated liver transaminase (ALT: 21.31%; AST: 13.11%)and proteinuria (24.59%). The increased serum creatinine levels were reversible and non-progressive. Of 38 patients with concomitant cyclosporine use, 12(31.8%)patients had two consecutive values >ULN, 10(26.3%)patients had two consecutive values >1.33 baseline values, but only 1(2.6%)patient's serum creatinine increased more than 1.33 baseline values and exceeded ULN. For both AST and ALT, no patients experienced two post- baseline values >5 ×ULN or >10 × ULN during the whole study. In AA patients with low baseline PLT count (less than 50 × 10(9)/L), there was no decrease for median PLT level during 12 months' treatment period.

CONCLUSIONSAA patients with iron overload could achieve satisfactory efficacy of iron chelation by deferasirox treatment. The drug was well tolerated with a clinically manageable safety profile and no major adverse events.

Anemia, Aplastic ; drug therapy ; Benzoates ; therapeutic use ; Blood Transfusion ; China ; Ferritins ; blood ; Humans ; Iron ; blood ; Iron Chelating Agents ; therapeutic use ; Iron Overload ; drug therapy ; Liver ; Prospective Studies ; Triazoles ; therapeutic use

BACKGROUND/AIMS: The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies. METHODS: We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib. RESULTS: Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-kappaB (NF-kappaB) and beta-catenin. CONCLUSIONS: We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-kappaB and beta-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML.
Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Benzoates/*pharmacology ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/*drug effects ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Imatinib Mesylate/*pharmacology ; Iron Chelating Agents/*pharmacology ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/metabolism ; Protein Kinase Inhibitors/*pharmacology ; Signal Transduction/drug effects ; Triazoles/*pharmacology

Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as one of the most promising biomarkers of renal epithelial injury. Numerous studies have presented the diagnostic and prognostic utility of urinary and plasma NGAL in patients with acute kidney injury, chronic kidney disease, renal injury after kidney transplantation, and other renal diseases. NGAL is a member of the lipocalin family that is abundantly expressed in neutrophils and monocytes/macrophages and is a mediator of the innate immune response. The biological significance of NGAL to hamper bacterial growth by sequestering iron-binding siderophores has been studied in a knock-out mouse model. Besides neutrophils, NGAL is detectable in most tissues normally encountered by microorganisms, and its expression is upregulated in epithelial cells during inflammation. A growing number of studies have supported the clinical utility of NAGL for detecting invasive bacterial infections. Several investigators including our group have reported that measuring NGAL can be used to help predict and manage urinary tract infections and acute pyelonephritis. This article summarizes the biology and pathophysiology of NGAL and reviews studies on the implications of NGAL in various renal diseases from acute kidney injury to acute pyelonephritis.
Acute Kidney Injury ; Animals ; Bacterial Infections ; Biomarkers ; Biology ; Epithelial Cells ; Humans ; Immunity, Innate ; Inflammation ; Kidney Diseases* ; Kidney Transplantation ; Kidney* ; Lipocalins* ; Mice ; Neutrophils* ; Plasma ; Pyelonephritis ; Renal Insufficiency, Chronic ; Research Personnel ; Siderophores ; Urinary Tract Infections

Pathogenic bacteria survive in iron-limited host environments by using several iron acquisition mechanisms. Acinetobacter baumannii, causing serious infections in compromised patients, produces an iron-chelating molecule, called acinetobactin, which is composed of equimolar quantities of 2,3-dihydroxybenzoic acid (DHBA), L-threonine, and N-hydroxyhistamine, to compete with host cells for iron. Genes that are involved in the production and transport of acinetobactin are clustered within the genome of A. baumannii. A recent study showed that entA, located outside of the acinetobactin gene cluster, plays important roles in the biosynthesis of the acinetobactin precursor DHBA and in bacterial pathogenesis. Therefore, understanding the genes that are associated with the biosynthesis and transport of acinetobactin in the bacterial genome is required. This review is intended to provide a general overview of the genes in the genome of A. baumannii that are required for acinetobactin biosynthesis and transport.
Acinetobacter baumannii* ; Bacteria ; Genome ; Genome, Bacterial ; Humans ; Iron ; Multigene Family ; Siderophores ; Threonine