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Charles M Dozois - One of the best experts on this subject based on the ideXlab platform.
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klebsiella pneumoniae Siderophores induce inflammation bacterial dissemination and hif 1α stabilization during pneumonia
Mbio, 2016Co-Authors: Victoria I Holden, Charles M Dozois, Paul Breen, Si Bastien Houle, Michael A BachmanAbstract:ABSTRACT Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of Siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of Siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro , Siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that Siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia. IMPORTANCE Klebsiella pneumoniae causes a wide range of bacterial diseases, including pneumonia, urinary tract infections, and sepsis. To cause infection, K. pneumoniae steals iron from its host by secreting Siderophores, small iron-chelating molecules. Classically, Siderophores are thought to worsen infections by promoting bacterial growth. In this study, we determined that siderophore-secreting K. pneumoniae causes lung inflammation and bacterial dissemination to the bloodstream independently of bacterial growth. Furthermore, we determined that siderophore-secreting K. pneumoniae activates a host protein, hypoxia inducible factor (HIF)-1α, and requires it for siderophore-dependent bacterial dissemination. Although HIF-1α can protect against some infections, it appears to worsen infection with K. pneumoniae. Together, these results indicate that bacterial Siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth. Therapies that disrupt production of Siderophores could provide a two-pronged attack against K. pneumoniae infection by preventing bacterial growth and preventing bacterial dissemination to the blood.
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Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia.
mBio, 2016Co-Authors: Victoria I Holden, Charles M Dozois, Paul Breen, Sébastien Houle, Michael A BachmanAbstract:Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of Siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of Siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro, Siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that Siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia.
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The Ins and Outs of siderophore mediated iron uptake by extra-intestinal pathogenic Escherichia coli.
Veterinary Microbiology, 2011Co-Authors: Amélie Garénaux, Mélissa Caza, Charles M DozoisAbstract:Extraintestinal pathogenic E. coli (ExPEC) are responsible for many infectious diseases in livestock, such as airsacculitis in poultry, acute mastitis in dairy animals and neonatal septicaemia and urinary tract infections (UTI) in pigs and cattle. In their animal hosts, ExPEC have to cope with low iron availability. By using different strategies, ExPEC strains are able to retrieve iron sequestered by host proteins. One of these strategies is the use of Siderophores, which are small secreted molecules with high affinity for iron. ExPEC are known to synthesize up to four different types of Siderophores: enterobactin, salmochelins, yersiniabactin and aerobactin. Steps required for iron acquisition by Siderophores include (1) siderophore synthesis in the cytoplasm, (2) siderophore secretion, (3) ferri-siderophore reception, (4) ferri-siderophore internalization and (5) iron release in the cytoplasm. Each siderophore has specific properties and may be differentially regulated to provide different advantages, potentially allowing ExPEC to adapt to different environmental conditions or to overcome host innate immunity. Iron acquisition by Siderophores plays a significant role in ExPEC virulence and, as it requires outer membrane receptors, it constitutes an interesting target for the development of vaccines that could be used to limit the number of infectious diseases due to ExPEC in livestock.
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Secretion, but not overall synthesis, of catecholate Siderophores contributes to virulence of extraintestinal pathogenic Escherichia coli.
Molecular Microbiology, 2011Co-Authors: Mélissa Caza, François Lépine, Charles M DozoisAbstract:Extraintestinal pathogenic Escherichia coli (ExPEC) use Siderophores to sequester iron during infection. Enterobactin and salmochelins are catecholate Siderophores produced by some ExPEC strains and other pathogenic enterobacteria. Siderophore export and synthesis mutants of avian ExPEC strain χ7122 were tested in a chicken infection model. In single-strain infections, siderophore-negative (ΔentDΔiuc), ΔentS and ΔentSΔiroC export mutants were attenuated in tissues and blood, whereas the ΔiroC export mutant was only attenuated in blood. Interestingly, the ΔentD mutant, producing only aerobactin, retained full virulence, and loss of entD in the ΔentSΔiroC mutant restored virulence. LC-MS/MS quantification of Siderophores in export mutants demonstrated that loss of entS impaired enterobactin and mono-glucosylated enterobactin secretion, whereas loss of iroC impaired di- and tri-glucosylated enterobactin secretion. Loss of entS and/or iroC resulted in intracellular accumulation and increased secretion of siderophore monomers. Catecholate siderophore export mutants also demonstrated decreased fitness in a co-challenge infection model. By contrast, catecholate siderophore synthesis mutants (ΔentD and ΔiroB) competed as well as the wild-type strain. Results establish that EntS and IroC mediate specific export of catecholate Siderophores and the role of these exporters for ExPEC virulence is contingent on enterobactin synthesis, which is not required when other Siderophores like aerobactin are functional.
Michael A Bachman - One of the best experts on this subject based on the ideXlab platform.
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klebsiella pneumoniae Siderophores induce inflammation bacterial dissemination and hif 1α stabilization during pneumonia
Mbio, 2016Co-Authors: Victoria I Holden, Charles M Dozois, Paul Breen, Si Bastien Houle, Michael A BachmanAbstract:ABSTRACT Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of Siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of Siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro , Siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that Siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia. IMPORTANCE Klebsiella pneumoniae causes a wide range of bacterial diseases, including pneumonia, urinary tract infections, and sepsis. To cause infection, K. pneumoniae steals iron from its host by secreting Siderophores, small iron-chelating molecules. Classically, Siderophores are thought to worsen infections by promoting bacterial growth. In this study, we determined that siderophore-secreting K. pneumoniae causes lung inflammation and bacterial dissemination to the bloodstream independently of bacterial growth. Furthermore, we determined that siderophore-secreting K. pneumoniae activates a host protein, hypoxia inducible factor (HIF)-1α, and requires it for siderophore-dependent bacterial dissemination. Although HIF-1α can protect against some infections, it appears to worsen infection with K. pneumoniae. Together, these results indicate that bacterial Siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth. Therapies that disrupt production of Siderophores could provide a two-pronged attack against K. pneumoniae infection by preventing bacterial growth and preventing bacterial dissemination to the blood.
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Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia.
mBio, 2016Co-Authors: Victoria I Holden, Charles M Dozois, Paul Breen, Sébastien Houle, Michael A BachmanAbstract:Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of Siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of Siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro, Siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that Siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia.
Victoria I Holden - One of the best experts on this subject based on the ideXlab platform.
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klebsiella pneumoniae Siderophores induce inflammation bacterial dissemination and hif 1α stabilization during pneumonia
Mbio, 2016Co-Authors: Victoria I Holden, Charles M Dozois, Paul Breen, Si Bastien Houle, Michael A BachmanAbstract:ABSTRACT Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of Siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of Siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro , Siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that Siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia. IMPORTANCE Klebsiella pneumoniae causes a wide range of bacterial diseases, including pneumonia, urinary tract infections, and sepsis. To cause infection, K. pneumoniae steals iron from its host by secreting Siderophores, small iron-chelating molecules. Classically, Siderophores are thought to worsen infections by promoting bacterial growth. In this study, we determined that siderophore-secreting K. pneumoniae causes lung inflammation and bacterial dissemination to the bloodstream independently of bacterial growth. Furthermore, we determined that siderophore-secreting K. pneumoniae activates a host protein, hypoxia inducible factor (HIF)-1α, and requires it for siderophore-dependent bacterial dissemination. Although HIF-1α can protect against some infections, it appears to worsen infection with K. pneumoniae. Together, these results indicate that bacterial Siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth. Therapies that disrupt production of Siderophores could provide a two-pronged attack against K. pneumoniae infection by preventing bacterial growth and preventing bacterial dissemination to the blood.
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Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia.
mBio, 2016Co-Authors: Victoria I Holden, Charles M Dozois, Paul Breen, Sébastien Houle, Michael A BachmanAbstract:Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of Siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of Siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro, Siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that Siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia.
Mohammad R. Seyedsayamdost - One of the best experts on this subject based on the ideXlab platform.
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Multiple Siderophores: bug or feature?
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry, 2018Co-Authors: Darcy L. Mcrose, Mohammad R. Seyedsayamdost, François M. M. MorelAbstract:It is common for bacteria to produce chemically diverse sets of small Fe-binding molecules called Siderophores. Studies of siderophore bioinorganic chemistry have firmly established the role of these molecules in Fe uptake and provided great insight into Fe complexation. However, we still do not fully understand why microbes make so many Siderophores. In many cases, the release of small structural variants or siderophore fragments has been ignored, or considered as an inefficiency of siderophore biosynthesis. Yet, in natural settings, microbes live in complex consortia and it has become increasingly clear that the secondary metabolite repertoires of microbes reflect this dynamic environment. Multiple siderophore production may, therefore, provide a window into microbial life in the wild. This minireview focuses on three biochemical routes by which multiple Siderophores can be released by the same organism—multiple biosynthetic gene clusters, fragment release, and precursor-directed biosynthesis—and highlights emergent themes related to each. We also emphasize the plurality of reasons for multiple siderophore production, which include enhanced iron uptake via synergistic siderophore use, microbial warfare and cooperation, and non-classical functions such as the use of Siderophores to take up metals other than Fe.
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quorum sensing and iron regulate a two for one siderophore gene cluster in vibrio harveyi
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Darcy L. Mcrose, Mohammad R. Seyedsayamdost, Oliver Baars, François M. M. MorelAbstract:The secretion of small Fe-binding molecules called Siderophores is an important microbial strategy for survival in Fe-limited environments. Siderophore production is often regulated by quorum sensing (QS), a microbial counting technique that allows organisms to alter gene expression based on cell density. However, the identity and quantities of Siderophores produced under QS regulation are rarely studied in the context of their roles in Fe uptake. We investigated the link between QS, Siderophores, and Fe uptake in the model marine organism Vibrio harveyi where QS is thought to repress siderophore production. We find that V. harveyi uses a single QS- and Fe-repressed gene cluster to produce both cell-associated Siderophores (amphiphilic enterobactins) as well as several related soluble Siderophores, which we identify and quantify using liquid chromatography-coupled (LC)-MS as well as tandem high-resolution MS (LC-HR-MS/MS). Measurements of siderophore production show that soluble Siderophores are present at ∼100× higher concentrations than amphi-enterobactin and that over the course of growth V. harveyi decreases amphi-enterobactin concentrations but accumulates soluble Siderophores. 55Fe radio-tracer uptake experiments demonstrate that these soluble Siderophores play a significant role in Fe uptake and that the QS-dictated concentrations of soluble Siderophores in stationary phase are near the limit of cellular uptake capacities. We propose that cell-associated and soluble Siderophores are beneficial to V. harveyi in different environmental and growth contexts and that QS allows V. harveyi to exploit "knowledge" of its population size to avoid unnecessary siderophore production.
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the siderophore metabolome of azotobacter vinelandii
Applied and Environmental Microbiology, 2016Co-Authors: Oliver Baars, François M. M. Morel, Xinning Zhang, Mohammad R. SeyedsayamdostAbstract:ABSTRACT In this study, we performed a detailed characterization of the siderophore metabolome, or “chelome,” of the agriculturally important and widely studied model organism Azotobacter vinelandii. Using a new high-resolution liquid chromatography-mass spectrometry (LC-MS) approach, we found over 35 metal-binding secondary metabolites, indicative of a vast chelome in A. vinelandii. These include vibrioferrin, a siderophore previously observed only in marine bacteria. Quantitative analyses of siderophore production during diazotrophic growth with different sources and availabilities of Fe showed that, under all tested conditions, vibrioferrin was present at the highest concentration of all Siderophores and suggested new roles for vibrioferrin in the soil environment. Bioinformatic searches confirmed the capacity for vibrioferrin production in Azotobacter spp. and other bacteria spanning multiple phyla, habitats, and lifestyles. Moreover, our studies revealed a large number of previously unreported derivatives of all known A. vinelandii Siderophores and rationalized their origins based on genomic analyses, with implications for siderophore diversity and evolution. Together, these insights provide clues as to why A. vinelandii harbors multiple siderophore biosynthesis gene clusters. Coupled with the growing evidence for alternative functions of Siderophores, the vast chelome in A. vinelandii may be explained by multiple, disparate evolutionary pressures that act on siderophore production.
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catecholate Siderophores protect bacteria from pyochelin toxicity
PLOS ONE, 2012Co-Authors: Conrado Adler, Mohammad R. Seyedsayamdost, Natalia Soledad Corbalan, Maria Fernanda Pomares, Ricardo E De Cristobal, Jon Clardy, Roberto Kolter, Paula A VincentAbstract:Background: Bacteria produce small molecule iron chelators, known as Siderophores, to facilitate the acquisition of iron from the environment. The synthesis of more than one siderophore and the production of multiple siderophore uptake systems by a single bacterial species are common place. The selective advantages conferred by the multiplicity of siderophore synthesis remains poorly understood. However, there is growing evidence suggesting that Siderophores may have other physiological roles besides their involvement in iron acquisition. Methods and Principal Findings: Here we provide the first report that pyochelin displays antibiotic activity against some bacterial strains. Observation of differential sensitivity to pyochelin against a panel of bacteria provided the first indications that catecholate Siderophores, produced by some bacteria, may have roles other than iron acquisition. A pattern emerged where only those strains able to make catecholate-type Siderophores were resistant to pyochelin. We were able to associate pyochelin resistance to catecholate production by showing that pyochelin-resistant Escherichia coli became sensitive when biosynthesis of its catecholate siderophore enterobactin was impaired. As expected, supplementation with enterobactin conferred pyochelin resistance to the entE mutant. We observed that pyochelin-induced growth inhibition was independent of iron availability and was prevented by addition of the reducing agent ascorbic acid or by anaerobic incubation. Addition of pyochelin to E. coli increased the levels of reactive oxygen species (ROS) while addition of ascorbic acid or enterobactin reduced them. In contrast, addition of the carboxylate-type siderophore, citrate, did not prevent pyochelin-induced ROS increases and their associated toxicity. Conclusions: We have shown that the catecholate siderophore enterobactin protects E. coli against the toxic effects of pyochelin by reducing ROS. Thus, it appears that catecholate Siderophores can behave as protectors of oxidative stress. These results support the idea that Siderophores can have physiological roles aside from those in iron acquisition.
Timothy A. Wencewicz - One of the best experts on this subject based on the ideXlab platform.
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emergence of ferrichelatase activity in a siderophore binding protein supports an iron shuttle in bacteria
ACS central science, 2020Co-Authors: Nathaniel P Endicott, Gerry Sann M. Rivera, Jinping Yang, Timothy A. WencewiczAbstract:Siderophores are small-molecule high-affinity multidentate chelators selective for ferric iron that are produced by pathogenic microbes to aid in nutrient sequestration and enhance virulence. In Gram-positive bacteria, the currently accepted paradigm in siderophore-mediated iron acquisition is that effluxed metal-free Siderophores extract ferric iron from biological sources and the resulting ferric siderophore complex undergoes diffusion-controlled association with a surface-displayed siderophore-binding protein (SBP) followed by ABC permease-mediated translocation across the cell envelope powered by ATP hydrolysis. Here we show that a more efficient paradigm is possible in Gram-positive bacteria where extracellular metal-free Siderophores associate directly with apo-SBPs on the cell surface and serve as non-covalent cofactors that enable the holo-SBPs to non-reductively extract ferric iron directly from host metalloproteins with so-called "ferrichelatase" activity. The resulting SBP-bound ferric siderophore complex is ready for import through an associated membrane permease and enzymatic turnover is achieved through cofactor replacement from the readily available pool of extracellular Siderophores. This new "iron shuttle" model closes a major knowledge gap in microbial iron acquisition and defines new roles of the siderophore and SBP as cofactor and enzyme, respectively, in addition to the classically accepted roles as a transport substrate and receptor pair. We propose the formal name "siderophore-dependent ferrichelatases" for this new class of catalytic SBPs.
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Immobilized FhuD2 Siderophore-Binding Protein Enables Purification of Salmycin Sideromycins from Streptomyces violaceus DSM 8286
2018Co-Authors: Gerry Sann M. Rivera, Catherine R. Beamish, Timothy A. WencewiczAbstract:Siderophores are a structurally diverse class of natural products common to most bacteria and fungi as iron(III)-chelating ligands. Siderophores, including trihydroxamate ferrioxamines, are used clinically to treat iron overload diseases and show promising activity against many other iron-related human diseases. Here, we present a new method for the isolation of ferrioxamine Siderophores from complex mixtures using affinity chromatography based on resin-immobilized FhuD2, a siderophore-binding protein (SBP) from Staphylococcus aureus. The SBP-resin enabled purification of charge positive, charge negative, and neutral ferrioxamine Siderophores. Treatment of culture supernatants from Streptomyces violaceus DSM 8286 with SBP-resin provided an analytically pure sample of the salmycins, a mixture of structurally complex glycosylated sideromycins (siderophore–antibiotic conjugates) with potent antibacterial activity toward human pathogenic Staphylococcus aureus (minimum inhibitory concentration (MIC) = 7 nM). Siderophore affinity chromatography could enable the rapid discovery of new siderophore and sideromycin natural products from complex mixtures to aid drug discovery and metabolite identification efforts in a broad range of therapeutic areas
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Acinetobactin Isomerization Enables Adaptive Iron Acquisition in Acinetobacter baumannii through pH-Triggered Siderophore Swapping.
ACS infectious diseases, 2015Co-Authors: Justin A. Shapiro, Timothy A. WencewiczAbstract:Pathogenic strains of Acinetobacter baumannii excrete multiple Siderophores that enhance iron scavenging from host sources. The oxazoline siderophore pre-acinetobactin undergoes an unusual non-enzymatic isomerization, producing the isoxazolidinone acinetobactin. In this study, we explored the kinetics, mechanism, and biological consequence of this siderophore swapping. Pre-acinetobactin is excreted to the extracellular space where the isomerization to acinetobactin occurs with a pH-rate profile consistent with 5-exo-tet cyclization at C5' with clean stereochemical inversion. Pre-acinetobactin persists at pH 7, matching each siderophore's pH preference for iron(III) chelation and A. baumannii growth promotion. Acinetobactin isomerization provides two Siderophores for the price of one, enabling A. baumannii to sequester iron over a broad pH range likely to be encountered during the course of an infection.
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Acinetobactin Isomerization Enables Adaptive Iron Acquisition in Acinetobacter baumannii through pH-Triggered Siderophore Swapping
2015Co-Authors: Justin A. Shapiro, Timothy A. WencewiczAbstract:Pathogenic strains of Acinetobacter baumannii excrete multiple Siderophores that enhance iron scavenging from host sources. The oxazoline siderophore pre-acinetobactin undergoes an unusual non-enzymatic isomerization, producing the isoxazolidinone acinetobactin. In this study, we explored the kinetics, mechanism, and biological consequence of this siderophore swapping. Pre-acinetobactin is excreted to the extracellular space where the isomerization to acinetobactin occurs with a pH-rate profile consistent with 5-exo-tet cyclization at C5′ with clean stereochemical inversion. Pre-acinetobactin persists at pH 7, matching each siderophore’s pH preference for iron(III) chelation and A. baumannii growth promotion. Acinetobactin isomerization provides two Siderophores for the price of one, enabling A. baumannii to sequester iron over a broad pH range likely to be encountered during the course of an infection
