Siderophore-mediated iron acquisition in the staphylococci

Iron is frequently a growth-limiting nutrient due to its propensity to interact with oxygen to form insoluble precipitates and, therefore, biological systems have evolved specialized uptake mechanisms to obtain this essential nutrient. Many pathogenic bacteria are capable of obtaining stringently sequestered iron from animal hosts by one or both of the following mechanisms: extraction of heme from host erythrocyte and serum hemoproteins, or through the use of high affinity, iron-scavenging molecules termed siderophores. This review summarizes our current knowledge of siderophore-mediated iron acquisition systems in the genus Staphylococcus.     

Crystal structure of hemoglobin protease, a heme binding autotransporter protein from pathogenic Escherichia coli

The acquisition of iron is essential for the survival of pathogenic bacteria, which have consequently evolved a wide variety of uptake systems to extract iron and heme from host proteins such as hemoglobin. Hemoglobin protease (Hbp) was discovered as a factor involved in the symbiosis of pathogenic Escherichia coli and Bacteroides fragilis, which cause intra-abdominal abscesses. Released from E. coli, this serine protease autotransporter degrades hemoglobin and delivers heme to both bacterial species. The crystal structure of the complete passenger domain of Hbp (110 kDa) is presented, which is the first structure from this class of serine proteases and the largest parallel beta-helical structure yet solved.     

Iron uptake mechanisms of pathogenic bacteria

Abstract: Most of the iron in a mammalian body is complexed with various proteins. Moreover, in response to infection, iron availability is reduced in both extracellular and intracellular compartments. Bacteria need iron for growth and successful bacterial pathogens have therefore evolved to compete successfully for iron in the highly iron-stressed environment of the host's tissues and body fluids. Several strategies have been identified among pathogenic bacteria, including reduction of ferric to ferrous iron, occupation of intracellular niches, utilisation of host iron compounds, and production of siderophores. While direct evidence that high affinity mechanisms for iron acquisition function as bacterial virulence determinants has been provided in only a small number of cases, it is likely that many if not all such systems play a central role in the pathogenesis of infection.     

The impact of iron on Listeria monocytogenes; inside and outside the host

As iron is vital for all cells, host sequestration of iron provides a significant barrier to bacterial infection. The absolute requirement for iron has driven the evolution of refined systems by which pathogenic bacteria such as Listeria monocytogenes can competitively acquire this element during host infection. This process is coordinated, at least partly, by the Ferric Uptake Regulator (Fur). Recent studies have identified loci within the listerial Fur-regulon and have characterized specific systems involved in iron uptake from various sources. This work has greatly advanced our knowledge of the mechanisms underpinning iron homeostasis in L. monocytogenes. A greater understanding of the molecular mechanisms by which pathogenic bacteria acquire iron is significant from both a food safety and public-health perspective.     

Iron uptake mechanisms as key virulence factors in bacterial fish pathogens

This review summarizes the current knowledge about iron uptake systems in bacterial fish pathogens and their involvement in the infective process. Like most animal pathogens, fish pathogens have evolved sophisticated iron uptake mechanisms some of which are key virulence factors for colonization of the host. Among these systems, siderophore production and heme uptake systems are the best studied in fish pathogenic bacteria. Siderophores like anguibactin or piscibactin, have been described in Vibrio and Photobacterium pathogens as key virulence factors to cause disease in fish. In many other bacterial fish pathogens production of siderophores was demonstrated but the compounds were not yet chemically characterized and their role in virulence was not determined. The role of heme uptake in virulence was not yet clearly elucidated in fish pathogens although there exist evidence that these systems are expressed in fish tissues during infection. The relationship of other systems, like Fe(II) transporters or the use of citrate as iron carrier, with virulence is also unclear. Future trends of research on all these iron uptake mechanisms in bacterial fish pathogens are also discussed.     

细菌铁离子摄取系统与宿主免疫

铁是绝大多数细菌生存所必需的营养物质,参与了许多重要的生命过程。病原菌为了在宿主体内生长繁殖建立感染,进化出了多种从宿主体内摄取铁元素的机制。但过量的铁也会通过Fenton反应对细胞产生毒性,所以铁的摄取必须受到严格的调控。宿主为抵抗感染采取多种手段限制病原菌对于自身铁的利用,同时铁摄取系统也可以作为抗菌治疗的靶点。     

革兰氏阴性菌血红素转运系统结构及功能特点

铁是大多数生物包括细菌生存的必需营养元素．对于感染宿主的致病细菌,血红素(heme/haem)可作为一种主要的铁来源．血红素转运系统在革兰氏阴性菌和革兰氏阳性菌中均有发现和鉴定,其转运机制在革兰氏阴性菌中有较为深入研究．革兰氏阴性菌血红素转运系统主要由分泌于细胞外的血红素载体(hemophore)、血红素受体、TonB ExbB ExbD复合物、ABC转运体、血红素降解蛋白和调控蛋白等结构单元组成．对参与该系统的各个蛋白结构特点以及它们之间的相互作用机制的讨论,有助于对病原菌致病机制的深入研究和抗菌新药的研发．     

TonB-dependent transporters and their occurrence in cyanobacteria

Background  

Different iron transport systems evolved in Gram-negative bacteria during evolution. Most of the transport systems depend on outer membrane localized TonB-dependent transporters (TBDTs), a periplasma-facing TonB protein and a plasma membrane localized machinery (ExbBD). So far, iron chelators (siderophores), oligosaccharides and polypeptides have been identified as substrates of TBDTs. For iron transport, three uptake systems are defined: the lactoferrin/transferrin binding proteins, the porphyrin-dependent transporters and the siderophore-dependent transporters. However, for cyanobacteria almost nothing is known about possible TonB-dependent uptake systems for iron or other substrates.     

Morphological plasticity as a bacterial survival strategy

Bacteria have evolved complex systems to maintain consistent cell morphologies. Nevertheless, in certain circumstances, bacteria alter this highly regulated process to transform into filamentous organisms. Accumulating evidence attributes important biological roles to filamentation in stressful environments, including, but not limited to, sites of interaction between pathogenic bacteria and their hosts. Filamentation could represent an intended response to specific environmental cues that promote survival amidst the threats of consumption and killing.     

The ‘Checkmate’ for Iron Between Human Host and Invading Bacteria: Chess Game Analogy

Iron is an essential nutrient for all living organisms with critical roles in many biological processes. The mammalian host maintains the iron requirements by dietary intake, while the invading pathogenic bacteria compete with the host to obtain those absorbed irons. In order to limit the iron uptake by the bacteria, the human host employs numerous iron binding proteins and withholding defense mechanisms that capture iron from the microbial invaders. To counteract, the bacteria cope with the iron limitation imposed by the host by expressing various iron acquisition systems, allowing them to achieve effective iron homeostasis. The armamentarium used by the human host and invading bacteria, leads to the dilemma of who wins the ultimate war for iron.     

Genetics and molecular biology of siderophore-mediated iron transport in bacteria.

The possession of specialized iron transport systems may be crucial for bacteria to override the iron limitation imposed by the host or the environment. One of the most commonly found strategies evolved by microorganisms is the production of siderophores, low-molecular-weight iron chelators that have very high constants of association for their complexes with iron. Thus, siderophores act as extracellular solubilizing agents for iron from minerals or organic compounds, such as transferrin and lactoferrin in the host vertebrate, under conditions of iron limitation. Transport of iron into the cell cytosol is mediated by specific membrane receptor and transport systems which recognize the iron-siderophore complexes. In this review I have analyzed in detail three siderophore-mediated iron uptake systems: the plasmid-encoded anguibactin system of Vibrio anguillarum, the aerobactin-mediated iron assimilation system present in the pColV-K30 plasmid and in the chromosomes of many enteric bacteria, and the chromosomally encoded enterobactin iron uptake system, found in Escherichia coli, Shigella spp., Salmonella spp., and other members of the family Enterobacteriaceae. The siderophore systems encoded by Pseudomonas aeruginosa, namely, pyochelin and pyoverdin, as well as the siderophore amonabactin, specified by Aeromonas hydrophila, are also discussed. The potential role of siderophore-mediated systems as virulence determinants in the specific host-bacteria interaction leading to disease is also analyzed with respect to the influence of these systems in the expression of other factors, such as toxins, in the bacterial virulence repertoire.     

Antagonistic control of microbial pathogens under iron limitations by siderophore producing bacteria in a chemostat setup

Certain bacteria develop iron chelation mechanisms that allow them to scavenge dissolved iron from the environment and to make it unavailable to competitors. This is achieved by producing siderophores that bind the iron which is later liberated internally in the cell. Under conditions of iron limitation, siderophore producing bacteria have therefore an antagonistic growth advantage over other species. This has been observed in particular in agricultural and aquacultural systems, as well as in food microbiology. We investigate here the possibility of a probiotic biocontrol strategy to eradicate a well established, often pathogenic, non-chelating population by supplementing the system with generally regarded as safe siderophore producing bacteria. Set in a chemostat setup, our modeling and simulation studies suggest that this is indeed possible in a finite time treatment.     

The role of iron-regulated genes in microbial pathogenesis

An important component of nonspecific defence of human or animal organisms against microbial invasion is attempt to withhold growth-essential iron from invading bacteria. To overcome the barrier bacterial iron uptake systems is derepressed at low iron concentrations. In many pathogenic and nonpathogenic bacteria the regulation of the corresponding genes depends on the regulatory protein Fur. For cloning Fur-regulated loci, methods based on affinity of Fur to the corresponding promoter sites are used.     

Emerging strategies in microbial haem capture

Gram-negative pathogenic bacteria have evolved novel strategies to obtain iron from host haem-sequestering proteins. These include the production of specific outer membrane receptors that bind directly to host haem-sequestering proteins, secreted haem-binding proteins (haemophores) that bind haem/haemoglobin/haemopexin and deliver the complex to a bacterial cell surface receptor and bacterial proteases that degrade haem-sequestering proteins. Once removed from haem-sequestering proteins, haem may be transported via the bacterial outer membrane receptor into the cell. Recent studies have begun to define the steps by which haem is removed from bacterial haem proteins and transported into the cell. This review describes recent work on the discovery and characterization of these systems. Reference is also made to the transport of haem in serum (via haemoglobin, haemoglobin/haptoglobin, haemopexin, albumin and lipoproteins) and to mechanisms of iron removal from the haem itself (probably via a haem oxygenase pathway in which the protoporphyrin ring is degraded). Haem protein-receptor interactions are discussed in terms of the criteria that govern protein-protein interactions in general, and connections between haem transport and the emerging field of metal transport via metallochaperones are outlined.     

Acid tolerance of gastrointestinal pathogens

The ability of pathogenic bacteria to survive in the face of host defense systems is intimately linked to virulence. This is exemplified by gastrointestinal pathogens that must survive exposure to extreme acid conditions within the stomach and organic acid conditions within the small intestine. These organisms have evolved complex systems to respond to acid stress, and recent work has revealed new genetic components involved in survival and virulence. Here, we review recent work on four gastrointestinal pathogens, focusing on studies that reveal both acid-inducible resistance systems and inherent (basal state) acid-resistance systems.     

Iron, infection, and neoplasia

In nearly all forms of life, the number and diversity of enzymes that contain iron or that depend on the presence of this metal for activity are impressive. Not surprisingly, chemical mechanisms have been evolved by many organisms that permit them to solubilize and acquire iron while at the same time depriving their competitors or their pathogens of this element. Proteins such as transferrin and lactoferrin that are employed by vertebrate hosts for iron transport and acquisition can, to some extent, withhold the metal from the siderophores of invading bacteria and fungi. Attempts also are made by animal hosts to withhold iron from protozoa and neoplastic cells. Unfortunately, pathogenic microorganisms have developed a variety of counter measures that are especially dangerous in hosts stressed by iron overload in specific fluids, tissues, or cells. In recent years, however, a number of possible methods and agents for strengthening iron-withholding defense have become apparent. Nearly 3,000 papers on various aspects of iron withholding are contained in the 18-year Medline Database and numerous reviews have been published since 1966. The present paper will focus on developments that have been reported within the past 2 1/2 years.     

Iron Acquisition and Transport in Staphylococcus aureus

Pathogenic Gram-positive bacteria encounter many obstacles in route to successful invasion and subversion of a mammalian host. As such, bacterial species have evolved clever ways to prevent the host from clearing an infection, including the production of specialized virulence systems aimed at counteracting host defenses or providing protection from host immune mechanisms. Positioned at the interface of bacteria/host interactions is the bacterial cell wall, a dynamic surface organelle that serves a multitude of functions, ranging from physiologic processes such as structural scaffold and barrier to osmotic lysis to pathogenic properties, for example the deposition of surface molecules and the secretion of cytotoxins. In order to succeed in a battle with host defenses, invading bacteria need to acquire the nutrient iron, which is sequestered within host tissues. A cell-wall based iron acquisition and import pathway was uncovered in Staphylococcus aureus. This pathway, termed the isd or iron-responsive surface determinant locus, consists of a membrane transporter, cell wall anchored heme-binding proteins, heme/haptoglobin receptors, two heme oxygenases, and sortase B, a transpeptidase that anchors substrate proteins to the cell wall. Identification of the isd pathway provides an additional function to the already bountiful roles the cell wall plays in bacterial pathogenesis and provides new avenues for therapeutics to combat the rise of antimicrobial resistance in S. aureus. This review focuses on the molecular attributes of this locus, with emphasis placed on the mechanism of iron transport and the role of such a system during infection.     

细菌金属离子外排系统及金属稳态调控

铁、铜、锌、锰等金属离子是各类生物体生存和增殖所必需的微量元素,可影响生物体内蛋白酶活性、免疫反应、生理过程和抗感染机制。细菌感染过程中,宿主可通过限制或提高体内环境中金属离子的浓度来抑制细菌增殖,与此同时,细菌进化出各种转运系统以适应宿主体内金属离子水平的变化。由于不同细菌的金属离子外排系统在结构和生化特性上存在变异,它们呈现出独特的金属离子外排模式。本文根据现有文献报道及本团队研究结果,对铁、铜、锌和锰离子的细菌外排系统进行讨论和总结,旨在综述目前对细菌金属离子稳态调控机制研究进展的认识,为深入理解细菌金属稳态调控相关机制提供参考。     

NEAT: a domain duplicated in genes near the components of a putative Fe3+ siderophore transporter from Gram-positive pathogenic bacteria

Background  

Iron uptake from the host is essential for bacteria that infect animals. To find potential targets for drugs active against pathogenic bacteria, we have searched all completely sequenced genomes of pathogenic bacteria for genes relevant for iron transport.