Siderophores (compound from the Ancient Greek nouns sídēros (σίδηρος)[1] and phoros (φορος)[2] meaning "iron carrier") are small, high-affinity iron chelating compounds secreted by grasses and microorganisms such as bacteria and fungi.[3][4][5][6] Siderophores are amongst the strongest soluble Fe3+ binding agents known.
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Iron is essential for almost all life, essential for processes such as respiration and DNA synthesis. Despite being one of the most abundant elements in the Earth’s crust, the bioavailability of iron in many environments such as the soil or sea is limited by the very low solubility of the Fe3+ ion. This is the predominant state of iron in aqueous, non-acidic, oxygenated environments. It accumulates in common mineral phases such as iron oxides and hydroxides (the minerals that are responsible for red and yellow soil colours) hence cannot be readily utilized by organisms.[7] Microbes release siderophores to scavenge iron from these mineral phases by formation of soluble Fe3+ complexes that can be taken up by active transport mechanisms. Many siderophores are nonribosomal peptides,[8] although several are biosynthesised independently.[9]
Siderophores are also important for some pathogenic bacteria for their acquisition of iron.[8] In mammalian hosts, iron is tightly bound to proteins such as hemoglobin, transferrin, lactoferrin and ferritin. The strict homeostasis of iron leads to a free concentration of about 10−24 mol L−1,[10] hence there are great evolutionary pressures put on pathogenic bacteria to obtain this metal. For example, the anthrax pathogen Bacillus anthracis releases two siderophores, bacillibactin and petrobactin, to scavenge ferric iron from iron proteins. While bacillibactin has been shown to bind to the immune system protein siderocalin,[11] petrobactin is assumed to evade the immune system and has been shown to be important for virulence in mice.[12]
Siderophores are amongst the strongest binders to Fe3+ known, with enterobactin being one of the strongest of these.[10] Because of this property, they have attracted interest from medical science in metal chelation therapy, with the siderophore desferrioxamine B gaining widespread use in treatments for iron poisoning and thalassemia.
Besides siderophores, some pathogenic bacteria produce hemophores (heme binding scavenging proteins) or have receptors that bind directly to iron/heme proteins.[13] In eukaryotes, other strategies to enhance iron solubility and uptake are the acidification of the surrounding (e.g. used by plant roots) or the extracellular reduction of Fe3+ into the more soluble Fe2+ ions.
Siderophores usually form a stable, hexadentate, octahedral complex with Fe3+ preferentially compared to other naturally occurring abundant metal ions, although if there are less than six donor atoms water can also coordinate. The most effective siderophores are those that have three bidentate ligands per molecule, forming a hexadentate complex and causing a smaller entropic change than that caused by chelating a single ferric ion with separate ligands. For a representative collection of siderophores see Studies and Syntheses of Siderophores, Microbial Iron Chelators, and Analogs as Potential Drug Delivery Agents by Marvin J. Miller.[14]
Fe3+ is a hard Lewis acid, preferring hard Lewis bases such as anionic or neutral oxygen to coordinate with. Microbes usually release the iron from the siderophore by reduction to Fe2+ which has little affinity to these ligands.[8]
Siderophores are usually classified by the ligands used to chelate the ferric iron. The majors groups of siderophores include the catecholates (phenolates), hydroxamates and carboxylates (e.g. derivatives of citric acid). Citric acid can also act as a siderophore.[15] The wide variety of siderophores may be due to evolutionary pressures placed on microbes to produce structurally different siderophores which cannot be transported by other microbes' specific active transport systems, or in the case of pathogens deactivated by the host organism.[5]
Examples of siderophores produced by various bacteria and fungi:
Hydroxamate siderophores
| Siderophore | Organism |
|---|---|
| ferrichrome | Ustilago sphaerogena |
| Desferrioxamine B | Streptomyces pilosus
Streptomyces coelicolor |
| Desferrioxamine E | Streptomyces coelicolor |
| fusarinine C | Fusarium roseum |
| ornibactin | Burkholderia cepacia |
Catecholate siderophores
| Siderophore | Organism |
|---|---|
| enterobactin | Escherichia coli
enteric bacteria |
| bacillibactin | Bacillus subtilis |
| vibriobactin | Vibrio cholerae |
Mixed ligands
| Siderophore | Organism |
|---|---|
| azotobactin | Azotobacter vinelandii |
| pyoverdine | Pseudomonas aeruginosa |
| yersiniabactin | Yersinia pestis |
Some poaceae (grasses) including wheat and barley produce a class of siderophores called phytosiderophores or mugineic acids.
In response to iron limitation in their environment, genes involved in microbe siderophore production and uptake are derepressed, leading to manufacture of siderophores and the appropriate uptake proteins. In bacteria, Fe2+-dependent repressors bind to DNA upstream to genes involved in siderophore in high intracellular iron concentrations. At low concentrations, Fe2+ dissociates from the repressor, which in turn dissociates from the DNA, leading to transcription of the genes. In gram-negative and AT-rich gram-positive bacteria, this is usually regulated by the Fur (ferric uptake regulator) repressor, whilst in GC-rich gram-positive bacteria (e.g. Actinobacteria) it is DtxR (diphtheria toxin repressor), so-called as the production of the dangerous diphtheria toxin by Corynebacterium diphtheriae is also regulated by this system.[8]
This is followed by excretion of the siderophore into the extracellular environment, where the siderophore acts to sequester and solubilize the iron.[16][17][18] Siderophores are then recognized by cell specific receptors on the outer membrane of the cell.[4][19] In fungi and other eukaryotes, the Fe-siderophore complex may be extracellularly reduced to Fe2+, whilst in many cases the whole Fe-siderophore complex is actively transported across the cell membrane. In gram-negative bacteria, these are transported into the periplasm via TonB-dependent receptors, and is transferred into the cytoplasm by ABC transporters.[8][14][20][20]
Once in the cytoplasm of the cell, the Fe3+-siderophore complex is usually reduced to Fe2+ to release the iron, especially in the case of "weaker" siderophore ligands such as hydroxamates and carboxylates. Siderophore decomposition or other biological mechanisms can also release iron.,[14] especially in the case of catecholates such as ferric-enterobactin, whose reduction potential is too low for reducing agents such as flavin adenine dinucleotide, hence enzymatic degradation is needed to release the iron.[10]
Siderophores have applications in medicine for iron and aluminum overload therapy and antibiotics for better targeting.[19] Understanding the mechanistic pathways of siderophores has led to opportunities for designing small-molecule inhibitors that block siderophore biosynthesis and therefore bacterial growth and virulence in iron-limiting environments.[21]
Siderophores are useful as drugs in facilitating iron mobilization in humans, especially in the treatment of iron diseases, due to their high affinity for iron.[22] One potentially powerful application is to use the iron transport abilities of siderophores to carry drugs into cells by preparation of conjugates between siderophores and antimicrobial agents. Because microbes recognize and utilize only certain siderophores, such conjugates are anticipated to have selective antimicrobial activity.[5]
Microbial iron transport (siderophore)-mediated drug delivery makes use of the recognition of siderophores as iron delivery agents in order to have the microbe assimilate siderophore conjugates with attached drugs. These drugs are lethal to the microbe and cause the microbe to apoptosise when it assimilates the siderophore conjugate.[5] Through the addition of the iron-binding functional groups of siderophores into antibiotics, their potency has been greatly increased. This is due to the siderophore-mediated iron uptake system of the bacteria.[4]
Poaceae (grasses) including agriculturally important species such as barley and wheat are able to efficiently sequester iron by releasing phytosiderophores via their root into the surrounding soil rhizosphere.[16] Chemical compounds produced by microorganisms in the rhizosphere can also increase the availability and uptake of iron. Plants such as oats are able to assimilate iron via these microbial siderophores. It has been demonstrated that plants are able to use the hydroxamate-type siderophores ferrichrome, rodotorulic acid and ferrioxamine B; the catechol-type siderophores, agrobactin; and the mixed ligand catechol-hydroxamate-hydroxy acid siderophores biosynthesized by saprophytic root-colonizing bacteria. All of these compounds are produced by rhizospheric bacterial strains, which have simple nutritional requirements, and are found in nature in soils, foliage, fresh water, sediments, and seawater.[23]
Fluorescent pseudomonads have been recognized as biocontrol agents against certain soil-borne plant pathogens. They produce yellow-green pigments (pyoverdines) which fluoresce under UV light and function as siderophores. They deprive pathogens of the iron required for their growth and pathogenesis.[24]
Alternative means of assimilating iron are surface reduction, lowering of pH, utilization of heme, or extraction of protein-complexed metal.[4]