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Mobilization of Iron Stored in Bacterioferritin Is Required for Metabolic Homeostasis in Pseudomonas aeruginosa
Punchi Hewage, Achala N. D. Fontenot, Leo Guidry, Jessie Weldeghiorghis, Thomas Mehta, Anil K. Donnarumma, Fabrizio Rivera, Mario
Punchi Hewage, Achala N. D.
Fontenot, Leo
Guidry, Jessie
Weldeghiorghis, Thomas
Mehta, Anil K.
Donnarumma, Fabrizio
Rivera, Mario
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Abstract
Iron homeostasis offers a significant bacterial vulnerability because pathogens obtain essential iron from their mammalian hosts, but host-defenses maintain vanishingly low levels of free iron. Although pathogens have evolved mechanisms to procure host-iron, these depend on well-regulated iron homeostasis. To disrupt iron homeostasis, our work has targeted iron mobilization from the iron storage protein bacterioferritin (BfrB) by blocking a required interaction with its cognate ferredoxin partner (Bfd). The blockade of the BfrB–Bfd complex by deletion of the bfd gene (Δbfd) causes iron to irreversibly accumulate in BfrB. In this study we used mass spectrometry and NMR spectroscopy to compare the proteomic response and the levels of key intracellular metabolites between wild type (wt) and isogenic ΔbfdP. aeruginosa strains. We find that the irreversible accumulation of unusable iron in BfrB leads to acute intracellular iron limitation, even if the culture media is iron-sufficient. Importantly, the iron limitation and concomitant iron metabolism dysregulation trigger a cascade of events that lead to broader metabolic homeostasis disruption, which includes sulfur limitation, phenazine-mediated oxidative stress, suboptimal amino acid synthesis and altered carbon metabolism.
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Date
2020-11-24
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MDPI
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Keywords
Iron homeostasis, Iron metabolism, Sulfur metabolism, Pseudomonas aeruginosa, Ferritin, Bacterioferritin, Ferredoxin, Proteomics
Citation
Punchi Hewage, A.N.D.; Fontenot, L.; Guidry, J.; Weldeghiorghis, T.; Mehta, A.K.; Donnarumma, F.; Rivera, M. Mobilization of Iron Stored in Bacterioferritin Is Required for Metabolic Homeostasis in Pseudomonas aeruginosa. Pathogens 2020, 9, 980. https://doi.org/10.3390/pathogens9120980