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Proteobactin and a yersiniabactin-related siderophore mediate iron acquisition in Proteus mirabilis
Stephanie D Himpsl1, Melanie M Pearson, Carl J Arewång
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Abstract:
Proteus mirabilis causes complicated urinary tract infections (UTIs). While the urinary tract is an iron-limiting environment, iron acquisition remains poorly characterized for this uropathogen. Microarray analysis of P. mirabilis HI4320 cultured under iron limitation identified 45 significantly upregulated genes (P ≤ 0.05) that represent 21 putative iron-regulated systems. Two gene clusters, PMI0229-0239 and PMI2596-2605, encode putative siderophore systems. PMI0229-0239 encodes a non-ribosomal peptide synthetase-independent siderophore system for producing a novel siderophore, proteobactin. PMI2596-2605 are contained within the high-pathogenicity island, originally described in Yersinia pestis, and encodes proteins with apparent homology and organization to those involved in yersiniabactin production and uptake. Cross-feeding and biochemical analysis shows that P. mirabilis is unable to utilize or produce yersiniabactin, suggesting that this yersiniabactin-related locus is functionally distinct. Only disruption of both systems resulted in an in vitro iron-chelating defect; demonstrating production and iron-chelating activity for both siderophores. These findings clearly show that proteobactin and the yersiniabactin-related siderophore function as iron acquisition systems. Despite the activity of both siderophores, only mutants lacking the yersiniabactin-related siderophore have reduced fitness in vivo. The fitness requirement for the yersiniabactin-related siderophore during UTI shows, for the first time, the importance of siderophore production in vivo for P. mirabilis.
Insights
Proteus mirabilis utilizes two siderophore systems, proteobactin and a yersiniabactin-related system, for iron acquisition during urinary tract infections (UTIs). The yersiniabactin-related system is crucial for bacterial fitness in vivo.
Area of Science:
- Microbiology
- Infectious Diseases
- Molecular Biology
Background:
- Proteus mirabilis is a significant cause of complicated urinary tract infections (UTIs).
- Iron acquisition is critical for bacterial survival in the iron-limited urinary tract environment.
- Iron acquisition mechanisms for P. mirabilis remain incompletely understood.
Purpose of the Study:
- To characterize the iron acquisition systems of Proteus mirabilis.
- To identify and investigate novel siderophore systems involved in iron uptake.
- To determine the in vivo relevance of identified siderophore systems during UTIs.
Main Methods:
- Microarray analysis to identify iron-regulated genes under iron limitation.
- Genetic manipulation (gene disruption) to study siderophore system function.
- In vitro biochemical assays (cross-feeding, iron-chelating activity) and in vivo fitness studies.
Main Results:
- Identified 21 putative iron-regulated systems, including two novel siderophore systems: proteobactin and a yersiniabactin-related system.
- Demonstrated that both proteobactin and the yersiniabactin-related siderophore contribute to iron acquisition in vitro.
- Showed that only the yersiniabactin-related siderophore system is essential for P. mirabilis fitness during in vivo UTIs.
Conclusions:
- Proteus mirabilis employs both proteobactin and a distinct yersiniabactin-related siderophore for iron acquisition.
- The yersiniabactin-related siderophore plays a critical role in P. mirabilis pathogenesis during UTIs.
- This study highlights the in vivo importance of siderophore production for uropathogenic bacteria.
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