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.

/pdf/siderophore-based-iron-acquisition-and-pathogen-control-2r9qlb86av.pdf

Siderophore-Based Iron Acquisition and Pathogen Control

The ability to acquire iron in vivo is essential for most microbial pathogens. Here we show that Aspergillus fumigatus does not have specific mechanisms for the utilization of host iron sources. However, it does have functional siderophore-assisted iron mobilization and reductive iron assimilation systems, both of which are induced upon iron deprivation. Abrogation of reductive iron assimilation, by inactivation of the high affinity iron permease (FtrA), has no effect on virulence in a murine model of invasive aspergillosis. In striking contrast, A. fumigatus L-ornithine-N5-monooxygenase (SidA), which catalyses the first committed step of hydroxamate-type siderophore biosynthesis, is absolutely essential for virulence. Thus, A. fumigatus SidA is an essential virulence attribute. Combined with the absence of a sidA ortholog-and the fungal siderophore system in general-in mammals, these data demonstrate that the siderophore biosynthetic pathway represents a promising new target for the development of antifungal therapies.

/pdf/siderophore-biosynthesis-but-not-reductive-iron-assimilation-3rg6p0vrxw.pdf

Siderophore Biosynthesis But Not Reductive Iron Assimilation Is Essential for Aspergillus fumigatus Virulence

A phylogenetic analysis of more than 350 multicopper oxidases (MCOs) from fungi, insects, plants, and bacteria provided the basis for a refined classification of this enzyme family into laccases sensu stricto (basidiomycetous and ascomycetous), insect laccases, fungal pigment MCOs, fungal ferroxidases, ascorbate oxidases, plant laccase-like MCOs, and bilirubin oxidases. Within the largest group of enzymes, formed by the 125 basidiomycetous laccases, the gene phylogeny does not strictly follow the species phylogeny. The enzymes seem to group at least partially according to the lifestyle of the corresponding species. Analyses of the completely sequenced fungal genomes showed that the composition of MCOs in the different species can be very variable. Some species seem to encode only ferroxidases, whereas others have proteins which are distributed over up to four different functional clusters in the phylogenetic tree.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-4658.2006.05247.x

Phylogenetic comparison and classification of laccase and related multicopper oxidase protein sequences

To acquire iron, all species have to overcome the problems of iron insolubility and toxicity. In response to low iron availability in the environment, most fungi excrete ferric iron-specific chelators—siderophores—to mobilize this metal. Siderophore-bound iron is subsequently utilized via the reductive iron assimilatory system or uptake of the siderophore-iron complex. Furthermore, most fungi possess intracellular siderophores as iron storage compounds. Molecular analysis of siderophore biosynthesis was initiated by pioneering studies on the basidiomycete Ustilago maydis, and has progressed recently by characterization of the relevant structural and regulatory genes in the ascomycetes Aspergillus nidulans and Neurospora crassa. In addition, significant advances in the understanding of utilization of siderophore-bound iron have been made recently in the yeasts Saccharomyces cerevisiae and Candida albicans as well as in the filamentous fungus A. nidulans. The present review summarizes molecular details of fungal siderophore biosynthesis and uptake, and the regulatory mechanisms involved in control of the corresponding genes.

Molecular genetics of fungal siderophore biosynthesis and uptake: the role of siderophores in iron uptake and storage

Microbial pathogens must compete with the iron-withholding defense systems of their host to acquire this essential nutrient Here, two high-affinity iron permease genes, CaFTR1 and CaFTR2, were isolated CaFTR1 expression was induced under iron-limited conditions and repressed when iron supply was sufficient, whereas the expression of CaFTR2 was regulated in a reversed manner Mutants lacking CaFTR1 but not CaFTR2 exhibited a severe growth defect in iron-deficient medium and were unable to establish systemic infection in mice Thus, CaFTR1-mediated iron-uptake mechanism constitutes a virulence factor of Candida albicans and may be a target for the development of anti-Candida therapies

https://science.sciencemag.org/content/sci/288/5468/1062.full.pdf

A high-affinity iron permease essential for Candida albicans virulence.

A multicopper oxidase gene from the human pathogenic yeast Candida albicans was isolated and characterized. An open reading frame of 1872 bp, designated CaFET3, was identified, encoding a predicted protein of 624 amino acids and a molecular mass of 70·5 kDa. The identity between the deduced amino acid sequences of CaFET3 and the Saccharomyces cerevisiae
FET3 gene is 55%. CaFET3 was localized on chromosome 6. A null mutant (fet3Δ/fet3Δ) was constructed by sequential gene disruption. Unlike the C. albicans SC5314 wild-type strain the fet3Δ mutant was unable to grow in low-iron medium. The lack of growth of a S. cerevisiae fet3Δ mutant in iron-limited medium was compensated by transformation with CaFET3. The null mutant strain showed no change in pathogenicity compared with the wild-type strain in the mouse model of systemic candidiasis.

A multicopper oxidase gene from Candida albicans: cloning, characterization and disruption.

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A multicopper oxidase gene from Candida albicans: cloning, characterization and disruption.