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

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.

Bafilomycins and concanamycins, two groups of the plecomacrolide-defined class of macrolide antibiotics, have recently been recognized as important tools for studying the physiological role of vacuolar-type, proton-translocating ATPases (V-ATPases) and ATPases with phosphorylated states (P-ATPases) in animal and plant cells as well as in yeast, fungi and bacteria. The following review will give an account of the classification and function of these antibiotics.

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Bafilomycins and concanamycins as inhibitors of V-ATPases and P-ATPases.

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

Aus Kulturfiltrat und Mycel eines Streptomyces viridochromogenes oder Streptomyces olivochromogenes nahestehenden Streptomyceten wurde neben Actidion eine neutrale, farblose, kristalline Verbindung C30H48O9, das Nonactin, isoliert, die chemisch wenig reaktiv ist und gegenuber den untersuchten Mikroorganismen unwirksam oder nur schwach wirksam war.

Stoffwechselprodukte von Actinomyceten. 3. Mitteilung. Nonactin

The macrolide-antibiotics are discussed in respect to their chemistry and biology. The single substances are listed. An investigation and classification of the streptomycetes producing macrolides, is added; the single species are critically revised. Relations are established between the producers and their products.

Zur Systematik der Actinomyceten

Die von verschiedenen Streptomyces-Arten gleichzeitig gebildeten roten Antibiotica Cinerubin A und B geben bei der sauren Hydrolyse drei Zucker und ein Aglykon C22H20O9. Fur das letztere wurde auf Grund physikalischer Eigenschaften und chemischer Reaktionen die Teilformel I abgeleitet. Das Aglykon der Cinerubine ist mit dem inzwischen von H. Brockmann und Mitarbb. isolierten und in seiner Konstitution aufgeklarten ϵ-Pyrromycinon identisch.1 .

Stoffwechselprodukte von Actinomyceten, XVI. Cinerubine

Structure Elucidation of Elaiophylin: Spectroscopy and Chemical Degradation



The structure of the antibiotic elaiophylin (azalomycin B) was elucidated by extended spectroscopic investigations and chemical degradation. Elaiophylin (26) is a macrodiolide with a 16membered dilactone ring. The synthesis of 7-acetoxy-6-ethyl-3-octanone (14), the acetyl derivative of an important degradation product, is described.

W. Keller-Schierlein

Papers

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

Stoffwechselprodukte von Actinomyceten. 3. Mitteilung. Nonactin

Zur Systematik der Actinomyceten

Stoffwechselprodukte von Actinomyceten, XVI. Cinerubine

Stoffwechselprodukte von Mikroorganismen. 202. Mitteilung. Strukturaufklärung von Elaiophylin: Spektroskopische Untersuchungen und Abbau