Hydroxamate siderophore mediated iron uptake in increases the bacterium’s susceptibility to antibiotics that target the cell wall. of infections and further diseases. Promising results for MAPK1 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. INTRODUCTION Most organisms require iron as an essential element in a variety of metabolic and informational cellular pathways. More than 100 enzymes acting in primary and secondary metabolism possess iron-containing cofactors such as iron-sulfur clusters or heme groups. The reversible Fe(II)/Fe(III) redox pair is best suited to catalyze a broad spectrum of redox reactions and to mediate electron chain transfer. Furthermore, several transcriptional (e.g., bacterial Fur and PerR) and posttranscriptional (e.g., mammalian iron regulatory proteins [IRPs]) regulators interact with iron to sense its intracellular level or the current status of oxidative stress in order to efficiently control the expression of a broad array of genes involved mainly in iron acquisition or reactive oxygen species (ROS) protection (131, 167). In special cases, the majority ( 80%) of the cellular proteome consists of iron-containing proteins that need iron as a rivet for overall structural and functional integrity as found in the archaebacterium (90). The cellular uptake of iron is restricted Dolasetron to its physiologically most relevant species, Fe(II) (ferrous iron) and Fe(III) (ferric iron). Fe(II) is soluble in aqueous solutions at neutral pH and is hence sufficiently available for living cells if the reductive state is maintained. Generally, Fe(II) can be taken up by ubiquitous divalent metal transporters. Systems for specific Fe(II) uptake are known in bacteria and yeast. However, in most microbial habitats, Fe(II) is oxidized to Fe(III) either spontaneously by reacting with molecular oxygen or enzymatically during assimilation and circulation in host organisms. In the environment, Fe(III) forms ferric oxide hydrate complexes (Fe2O3 hemophore system of uses heme-loaded hemopexin as specific heme/iron source, while the system of several other gram-negative bacteria uses heme from various sources. However, the hemophore systems are restricted to heme iron sources, making them minimally useful under conditions of low heme availability. In contrast, another indirect strategy is capable of exploiting all available iron sources independent of their nature, thus making it the most widespread and most successful mechanism of high-affinity iron acquisition in the microbial world. In analogy to the hemophore system, it is based on a shuttle mechanism that, however, uses small-molecule compounds called siderophores (generally 1 kDa) as high-affinity ferric iron chelators. Siderophore-dependent iron acquisition pathways can be found among a broad spectrum of prokaryotic and eukaryotic microbes (and even in higher plants) and show a high variety in structure and function of the involved components. The common theme is the production of one or more siderophores by cells during periods of iron starvation (which means that the Dolasetron intracellular iron concentration drops below the threshold of about 10?6 M, which is critical for microbial growth). Secreted siderophores form extracellular Fe(III) complexes with stabilities ranging over about 30 orders of magnitude Dolasetron for different siderophores. Next, either the iron-charged siderophore is taken up by ferric-chelate-specific transporters or siderophore-bound Fe(III) undergoes reduction Dolasetron to Fe(II), which is catalyzed by free extracellular or membrane-standing ferric-chelate reductases. A common advantage for cells is the utilization of xenosiderophores, which means that they possess ferric-chelate reductases and/or uptake systems for siderophores not synthesized by themselves. Baker’s yeast, for example, refrains completely from siderophore production but is capable of utilizing several exogenous siderophores as iron sources. If not already released extracytoplasmatically, the iron has to be removed from the Fe-siderophore complex in the cytosol. This is mediated either by intracellular ferric-siderophore reductases or, in a few cases, by ferric-siderophore hydrolases. The following intracellular iron channeling is only partially known. It is uncertain whether iron delivered into the microbial cell could be used immediately for metabolic and regulatory functions such as iron-sulfur cluster assembly and iron-dependent gene expression, respectively, or if intermediate storage has to precede. Several components are involved in iron storage, such as ferritin-like proteins, which either are heme free or, as in the case of bacterioferritins, contain a heme b.