Summary: High-affinity iron acquisition is mediated by siderophore-dependent pathways in the majority of pathogenic and nonpathogenic bacteria and fungi. Considerable progress has been made in characterizing and understanding mechanisms of siderophore synthesis, secretion, iron scavenging, and siderophore-delivered iron uptake and its release. The regulation of siderophore pathways reveals multilayer networks at the transcriptional and posttranscriptional levels. Due to the key role of many siderophores during virulence, coevolution led to sophisticated strategies of siderophore neutralization by mammals and (re)utilization by bacterial pathogens. Surprisingly, hosts also developed essential siderophore-based iron delivery and cell conversion pathways, which are of interest for diagnostic and therapeutic studies. In the last decades, natural and synthetic compounds have gained attention as potential therapeutics for iron-dependent treatment of infections and further diseases. Promising results for pathogen inhibition were obtained with various siderophore-antibiotic conjugates acting as “Trojan horse” toxins and siderophore pathway inhibitors. In this article, general aspects of siderophore-mediated iron acquisition, recent findings regarding iron-related pathogen-host interactions, and current strategies for iron-dependent pathogen control will be reviewed. Further concepts including the inhibition of novel siderophore pathway targets are discussed.

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Siderophore-Based Iron Acquisition and Pathogen Control

Chemistry and biology of siderophores.

http://pubs.acs.org/doi/pdf/10.1021/cr400460s

Metallodrugs in Medicinal Inorganic Chemistry

Enzymic analysis of steroid hormones.

For several years now, the metabolites of Actinomycetes have been under study in the research laboratories of the Swiss Federal Institute of Technology in Zurich and of CIBA Limited in Basle. In the course of these studies, numerous compounds have been isolated which contain complexbound trivalent iron and which are brownish-red in color. By reference to the effects they exert, these naturally occurring substances can be subdivided into two groups : the sideromycins and the sideramines.' The sideromycins are antibiotics, whereas the sideramines specifically antagonize the antibacterial properties of the sideromycins. The sideramines also possess growth-promoting properties and appear to exert an important function in the iron metabolism of microorganisms, possibly acting as iron donors in the incorporation of iron in the porphyrin systems. Among the various sideramines obtained from Streptomyces pilosus, the principal product is the so-called ferrioxamine B.?.$ The complex-bound trivalent iron contained in ferrioxamine B can be removed by chemical means, thus yielding the colorless, crystalline substance to be discussed here: desferrioxamine B.'  Desferrioxamine is composed of one molecule of acetic acid, two molecules of succinic acid, and three molecules of 1-amino-5-hydroxylaminopentane. The organic units of which desferrioxamine is built up are interlinked to form a chain, in which there are three hydroxamic acid groups inside, and one free amino group a t the end. The free amino group accounts for the basic character of the compound, which enables i t to form salts with organic and inorganic acids (FIGURE 1). When a ferric ion comes into contact with desferrioxamine, the straightchained molecule twines itself around the ion, becoming attached to the latter by means of its three hydroxamic acid groups (FIGURE 2 ) . The iron is thus surrounded by a shell of organic material, which results in an iron complex of very great stability. The stability constants for various desferrioxamine-metal complexes compared with the constants for other chelating agents are listed in TABLE l.596 The higher the constant, the more stable the complex. The highest figure here, lo:{', is for the iron complex of desferrioxamine. All the other constants for this compound are lower by at least 10.' This means that desferrioxamine is not only the most potent, but also by far the most spe-

The biochemistry of desferrioxamine and its relation to iron metabolism.

Ferrioxamine B, the main sideramine type growth factor isolated from cultures of Streptomyces pilosus ETTLINGERet al., is a racemic trihydroxamate-iron(III) complex of the compound IV. The possible configurations for the iron(III) complex are Va–e.

Stoffwechselprodukte von Actinomyceten. 27. Mitteilung. Über die Konstitution von Ferrioxamin B

A new group of iron-containing metabolites, with growth stimulating properties for a number of microorganisms, has been isolated from streptomycetes and namedferrioxamines. It is proposed to include them, together with some known substances, like ferrichrome, coprogen and the terregens factor, which either contain or bind iron, in a new class of growth factors, thesideramines. The biological property of the sideramines is counteracted by iron-containing antibiotics from streptomycetes, thesideromycins. They comprise, besides known products like grisein and albomycin, two new groups of antibiotics, among them the highly potentferrimycins.

[On iron-containing growth factors, sideramines, and their antagonists, the iron-containing antibiotics, sideromycins].

Isolation and properties of the ferrioxamines A, B, C, D1, D2, E and F, iron containing growth factors belonging to the group of the sideramines, are described.

Stoffwechselprodukte von Actinomyceten. 26. Mitteilung. Über die Isolierung und Charakterisierung der Ferrioxamine A—F, neuer Wuchsstoffe der Sideramin‐Gruppe

7-Aminocephalosporanic acid or esters thereof are prepared either by intramolecular aminolysis of esters of the antibiotic cephalosporin C or via imino-ethers derived from the latter.



A simple procedure for the preparation of 7-aminocephalosporanic acid in high yield is described.

Modifikationen von Antibiotika. 2. Mitteilung [1]. Über die Darstellung von 7‐Amino‐cephalosporansäure

A new crystalline substance has been isolated from hog adrenals in a yield of about 30 mg per 1000 kg glands. It appears to act under certain biological conditions as a sodium excreting factor. This compound is shown to be 3β,16α-dihydroxy-allopregnan-20-one; several syntheses of it as well as a number of derivatives are described.

E. Vischer

Papers

Stoffwechselprodukte von Actinomyceten. 27. Mitteilung. Über die Konstitution von Ferrioxamin B

[On iron-containing growth factors, sideramines, and their antagonists, the iron-containing antibiotics, sideromycins].

Stoffwechselprodukte von Actinomyceten. 26. Mitteilung. Über die Isolierung und Charakterisierung der Ferrioxamine A—F, neuer Wuchsstoffe der Sideramin‐Gruppe

Modifikationen von Antibiotika. 2. Mitteilung [1]. Über die Darstellung von 7‐Amino‐cephalosporansäure

Isolierung, Konstitution und Synthese eines neuen Steroides aus Nebennieren. Über Steroide, 155. Mitteilung