Nfu facilitates the maturation of iron-sulfur proteins and participates in virulence in Staphylococcus aureus.

Mashruwala AA, Pang YY, Rosario-Cruz Z, Chahal HK, Benson MA, Mike LA, Skaar EP, Torres VJ, Nauseef WM, Boyd JM
Mol Microbiol. 2015 95 (3): 383-409

PMID: 25388433 · PMCID: PMC4428306 · DOI:10.1111/mmi.12860

The acquisition and metabolism of iron (Fe) by the human pathogen Staphylococcus aureus is critical for disease progression. S. aureus requires Fe to synthesize inorganic cofactors called iron-sulfur (Fe-S) clusters, which are required for functional Fe-S proteins. In this study we investigated the mechanisms utilized by S. aureus to metabolize Fe-S clusters. We identified that S. aureus utilizes the Suf biosynthetic system to synthesize Fe-S clusters and we provide genetic evidence suggesting that the sufU and sufB gene products are essential. Additional biochemical and genetic analyses identified Nfu as an Fe-S cluster carrier, which aids in the maturation of Fe-S proteins. We find that deletion of the nfu gene negatively impacts staphylococcal physiology and pathogenicity. A nfu mutant accumulates both increased intracellular non-incorporated Fe and endogenous reactive oxygen species (ROS) resulting in DNA damage. In addition, a strain lacking Nfu is sensitive to exogenously supplied ROS and reactive nitrogen species. Congruous with ex vivo findings, a nfu mutant strain is more susceptible to oxidative killing by human polymorphonuclear leukocytes and displays decreased tissue colonization in a murine model of infection. We conclude that Nfu is necessary for staphylococcal pathogenesis and establish Fe-S cluster metabolism as an attractive antimicrobial target.

© 2014 John Wiley & Sons Ltd.

MeSH Terms (19)

Aconitate Hydratase Animals Disease Models, Animal DNA Damage Humans Iron Iron-Sulfur Proteins Mice Multigene Family Mutation Neutrophils Oxidation-Reduction Protein Binding Reactive Nitrogen Species Reactive Oxygen Species Staphylococcal Infections Staphylococcus aureus Sulfur Virulence

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