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Siderophore-based iron acquisition and pathogen control.

ABSTRACT: 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.

SUBMITTER: Miethke M

PROVIDER: S-EPMC2168645 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Siderophore-based iron acquisition and pathogen control.

Miethke Marcus M Marahiel Mohamed A MA

Microbiology and molecular biology reviews : MMBR 20070901 3

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 ...[more]

PMID: 17804665

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Project description:Klebsiella pneumoniae is rapidly acquiring resistance to all known antibiotics, including carbapenems. Multilocus sequence type ST258 (sequence type 258), carrying a gene encoding the K. pneumoniae carbapenemase (blaKPC) on a transmissible plasmid, is the most prevalent carbapenem-resistant Enterobacteriaceae (CRE) in the United States and has disseminated worldwide. Previously, whole-genome sequencing identified core genome single nucleotide variants that divide ST258 into two distinct clades, ST258a and ST258b. Furthermore, a subset of ST258b strains have a 347-base deletion within the enterobactin (Ent) exporter gene entS Despite the predicted inability of these strains to secrete the siderophore Ent, this clade is prevalent among clinical isolates, indicating that a full-length entS gene is not necessary for infection. To compare the transcriptional responses of ST258 subtypes to iron limitation, we performed transcriptome sequencing (RNA-Seq) in minimal medium alone or supplemented with iron or human serum and measured gene expression patterns. Iron limitation induced differential expression of distinct iron acquisition pathways when comparing ST258a and ST258b strains, including the upregulation of the hemin transport operon in entS partial deletion isolates. To measure how K. pneumoniae strains vary in iron chelation and siderophore production, we performed in vitro chrome azurol S (CAS) and Arnow assays as well as mass spectrometry. We determined that both ST258a and ST258b strains grow under iron-depleted conditions, can utilize hemin for growth, and secrete Ent, despite the partial entS deletion in a subset of ST258b strains. All carbapenem-resistant (CR) K. pneumoniae strains tested were susceptible to growth inhibition by the Ent-sequestering innate immune protein lipocalin 2.IMPORTANCE Carbapenem-resistant Enterobacteriaceae, including K. pneumoniae, are a major health care concern worldwide because they cause a wide range of infection and are resistant to all or nearly all antibiotics. To cause infection, these bacteria must acquire iron, and a major mechanism of acquiring iron is by secreting a molecule called enterobactin that strips iron from host proteins. However, a subset of carbapenem-resistant K. pneumoniae strains that lack a portion of the entS gene that is required for enterobactin secretion was recently discovered. To understand how these mutant strains obtain iron, we studied their transcriptional responses, bacterial growth, and enterobactin secretion under iron-limited conditions. We found that strains both with mutated and intact entS genes grow under iron-limiting conditions, secrete enterobactin, and utilize an alternate iron source, hemin, for growth. Our data indicate that carbapenem-resistant K. pneumoniae can use varied methods for iron uptake during infection.

Project description:Many bacteria secrete siderophores to enhance iron uptake under iron-restricted conditions. In this study, we found that Cupriavidus necator JMP134, a well-known aromatic pollutant-degrading bacterium, produces an unknown carboxylate-type siderophore named cupriabactin to overcome iron limitation. Using genome mining, targeted mutagenesis, and biochemical analysis, we discovered an operon containing six open reading frames (cubA-F) in the C. necator JMP134 genome that encodes proteins required for the biosynthesis and uptake of cupriabactin. As the dominant siderophore of C. necator JMP134, cupriabactin promotes the growth of C. necator JMP134 under iron-limited conditions via enhanced ferric iron uptake. Furthermore, we demonstrated that the iron concentration-dependent expression of the cub operon is mediated by the ferric uptake regulator (Fur). Physiological analyses revealed that the cupriabactin-mediated iron acquisition system influences swimming motility, biofilm formation, and resistance to oxidative and aromatic compound stress in C. necator JMP134. In conclusion, we identified a carboxylate-type siderophore named cupriabactin, which plays important roles in iron scavenging, bacterial motility, biofilm formation, and stress resistance.IMPORTANCE Since siderophores have been widely exploited for agricultural, environmental, and medical applications, the identification and characterization of new siderophores from different habitats and organisms will have great beneficial applications. Here, we identified a novel siderophore-producing gene cluster in C. necator JMP134. This gene cluster produces a previously unknown carboxylate siderophore, cupriabactin. Physiological analyses revealed that the cupriabactin-mediated iron acquisition system influences swimming motility, biofilm formation, and oxidative stress resistance. Most notably, this system also plays important roles in increasing the resistance of C. necator JMP134 to stress caused by aromatic compounds, which provide a promising strategy to engineer more efficient approaches to degrade aromatic pollutants.

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Siderophore-based iron acquisition and pathogen control.

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Siderophore-based iron acquisition and pathogen control.

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