The role of transition metal transporters for iron, zinc, manganese, and copper in the pathogenesis of Yersinia pestis

Perry, Robert D.; Bobrov, Alexander G.; Fetherston, Jacqueline D.

doi:10.1039/c4mt00332b

Cited by 50 publications

(46 citation statements)

References 118 publications

(358 reference statements)

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“…The need for multiple iron transport systems for optimal growth in different environments has been noted for other pathogens. In Yersinia pestis, the siderophore yersiniabactin is essential for the early stages of bubonic plague but is not needed for septicemic infection (44). Y. pestis has multiple ferrous iron transporters, including Feo, Yfe, and Fet.…”

Section: Discussionmentioning

confidence: 99%

Nonredundant Roles of Iron Acquisition Systems in Vibrio cholerae

et al. 2016

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Vibrio cholerae, the causative agent of the severe diarrheal disease cholera, thrives in both marine environments and the human host. To do so, it must encode the tools necessary to acquire essential nutrients, including iron, under these vastly different conditions. A number of V. cholerae iron acquisition systems have been identified; however, the precise role of each system is not fully understood. To test the roles of individual systems, we generated a series of mutants in which only one of the four systems that support iron acquisition on unsupplemented LB agar, Feo, Fbp, Vct, and Vib, remains functional. Analysis of these mutants under different growth conditions showed that these systems are not redundant. The strain carrying only the ferrous iron transporter Feo grew well at acidic, but not alkaline, pH, whereas the ferric iron transporter Fbp promoted better growth at alkaline than at acidic pH. A strain defective in all four systems (null mutant) had a severe growth defect under aerobic conditions but accumulated iron and grew as well as the wild type in the absence of oxygen, suggesting the presence of an additional, unidentified iron transporter in V. cholerae. In support of this, the null mutant was only moderately attenuated in an infant mouse model of infection. While the null mutant used heme as an iron source in vitro, we demonstrate that heme is not available to V. cholerae in the infant mouse intestine. The Gram-negative bacterium Vibrio cholerae has an absolute requirement for iron (1). Despite the prevalence of iron within its environmental niches and human host, most of this iron is not readily available. Iron occurs naturally as oxidized (ferric) or reduced (ferrous) iron (2). Ferric iron(III), found in oxygenated environments at neutral to alkaline pH, has very low water solubility and forms large insoluble complexes. Studies of ocean water have found iron to be the limiting nutrient for microbial growth (3). Soluble, ferrous iron(II) is more prevalent under the anoxic conditions that V. cholerae may encounter while colonizing the human host. However, access to iron in the host is limited due to competition with other microbes on host surfaces, as well as sequestration by high-affinity iron-binding host proteins such as transferrin and lactoferrin (4-7). Despite the challenges of obtaining iron in these various environments, V. cholerae is proficient in growth in both marine and host environments.The V. cholerae genome encodes multiple iron acquisition systems, which each transport a specific form of iron and may thus optimize iron acquisition in the various niches that V. cholerae inhabits (8-12). These include genes for the synthesis (vib) and utilization (viu) of vibriobactin, a siderophore that is secreted into the environment, where it binds ferric iron with extremely high affinity (9,(13)(14)(15). Ferrivibriobactin is bound by the outer membrane receptor ViuA (16,17) and is transported across the outer membrane in a process that requires either of two energy transduction systems, To...

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Section: Discussionmentioning

confidence: 99%

Nonredundant Roles of Iron Acquisition Systems in Vibrio cholerae

et al. 2016

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“…In uropathogenic E. coli (UPEC), loss of ZnuA and ZupT (ZRT-, IRT-like Protein family) proteins decreased the bacterial load in the murine urinary tract and kidneys in both a single-strain infection and when the mutant was coinfected with the wild type strain [31]. In Y. pestis , deletion of irp2 , the Ybt siderophore synthetase, in the znuABC mutant background resulted in a significant loss of virulence due to a defect in zinc acquisition [32,33]. While the znuABC mutant has a severe in vitro growth defect, the irp2 znuABC mutant is attenuated in the septicemic plague mouse model [32].…”

Section: Introductionmentioning

confidence: 99%

“…While the znuABC mutant has a severe in vitro growth defect, the irp2 znuABC mutant is attenuated in the septicemic plague mouse model [32]. Further, zinc uptake in Y. pestis is a concerted effort between components of the Ybt system, ZnuABC, and possibly a second high-affinity zinc transporter, yet to be identified, which all contribute to virulence [33,34]. During coinfections of Acinetobacter baumannii , an opportunistic and nosocomial pathogen, the loss of the TMD strain results in wildtype outcompeting the znuB mutant for colonization in lungs and livers of C57BL/6 mice [35].…”

Section: Introductionmentioning

confidence: 99%

Selective substrate uptake: The role of ATP-binding cassette (ABC) importers in pathogenesis

Tanaka

Song

Mason

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

135

102

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The uptake of nutrients, including metals, amino acids and peptides are required for many biological processes. Pathogenic bacteria scavenge these essential nutrients from microenvironments to survive within the host. Pathogens must utilize a myriad of mechanisms to acquire these essential nutrients from the host while mediating the effects of toxicity. Bacteria utilize several transport proteins, including ATP-binding cassette (ABC) transporters to import and expel substrates. ABC transporters, conserved across all organisms, are powered by the energy from ATP to move substrates across cellular membranes. In this review, we will focus on nutrient uptake, the role of ABC importers at the host-pathogen interface, and explore emerging therapies to combat pathogenesis. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain.

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“…Nevertheless, there are evidences that siderophores can chelate also other metals with physiological relevance, e.g. the siderophore yersiniabactin was recently found to sequester extracellular copper to protect uropathogenic Escherichia coli from copper toxicity during human infection [19], while some siderophores appear to be involved in uptake of various non-iron metals such as yersiniabactin in zinc uptake by Yersina pestis [20,21]. Due to the indispensability of siderophore-mediated iron acquisition, this system is hijacked during microbial competition, e.g.…”

Section: Microbial Siderophoresmentioning

confidence: 99%

“…Due to the indispensability of siderophore-mediated iron acquisition, this system is hijacked during microbial competition, e.g. the outer membrane ferrichrome-type siderophore receptor of E. coli serves also as receptor for various bacteriophages [22] and naturally evolved siderophore-antibiotic conjugates, termed sideromycins, in which a bactericidal warhead is attached to a siderophore moiety [20,21]. For instance, albomycins comprise a hydroxamate siderophore unit, reminiscent of those found in fungal ferrichromes, and bactericidal unit that inhibits seryl-tRNA synthetase.…”

Section: Microbial Siderophoresmentioning

confidence: 99%

Siderophores for molecular imaging applications

Petřík

Zhai

Haas

et al. 2016

Clin Transl Imaging

110

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This review covers publications on siderophores applied for molecular imaging applications, mainly for radionuclide-based imaging. Siderophores are low molecular weight chelators produced by bacteria and fungi to scavenge essential iron. Research on these molecules has a continuing history over the past 50 years. Many biomedical applications have been developed, most prominently the use of the siderophore desferrioxamine (DFO) to tackle iron overload related diseases. Recent research described the upregulation of siderophore production and transport systems during infection. Replacing iron in siderophores by radionuclides, the most prominent Ga-68 for PET, opens approaches for targeted imaging of infection; the proof of principle has been reported for fungal infections using 68 Ga-triacetylfusarinine C (TAFC). Additionally, fluorescent siderophores and therapeutic conjugates have been described and may be translated to optical imaging and theranostic applications. Siderophores have also been applied as bifunctional chelators, initially DFO as chelator for Ga-67 and more recently for Zr-89 where it has become the standard chelator in Immuno-PET. Improved DFO constructs and bifunctional chelators based on cyclic siderophores have recently been developed for Ga-68 and Zr-89 and show promising properties for radiopharmaceutical development in PET. A huge potential from basic biomedical research on siderophores still awaits to be utilized for clinical and translational imaging.

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The role of transition metal transporters for iron, zinc, manganese, and copper in the pathogenesis of Yersinia pestis

Cited by 50 publications

References 118 publications

Nonredundant Roles of Iron Acquisition Systems in Vibrio cholerae

Nonredundant Roles of Iron Acquisition Systems in Vibrio cholerae

Selective substrate uptake: The role of ATP-binding cassette (ABC) importers in pathogenesis

Siderophores for molecular imaging applications

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