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Results: 1 to 5 of 5

Publication Record


A Small-Molecule Inhibitor of Iron-Sulfur Cluster Assembly Uncovers a Link between Virulence Regulation and Metabolism in Staphylococcus aureus.
Choby JE, Mike LA, Mashruwala AA, Dutter BF, Dunman PM, Sulikowski GA, Boyd JM, Skaar EP
(2016) Cell Chem Biol 23: 1351-1361
MeSH Terms: Aconitate Hydratase, Anti-Bacterial Agents, Bacterial Proteins, Drug Discovery, Humans, Iron-Sulfur Proteins, Protein Kinases, Signal Transduction, Small Molecule Libraries, Staphylococcal Infections, Staphylococcus aureus, Transcription Factors, Virulence, Virulence Factors
Show Abstract · Added April 8, 2017
The rising problem of antimicrobial resistance in Staphylococcus aureus necessitates the discovery of novel therapeutic targets for small-molecule intervention. A major obstacle of drug discovery is identifying the target of molecules selected from high-throughput phenotypic assays. Here, we show that the toxicity of a small molecule termed '882 is dependent on the constitutive activity of the S. aureus virulence regulator SaeRS, uncovering a link between virulence factor production and energy generation. A series of genetic, physiological, and biochemical analyses reveal that '882 inhibits iron-sulfur (Fe-S) cluster assembly most likely through inhibition of the Suf complex, which synthesizes Fe-S clusters. In support of this, '882 supplementation results in decreased activity of the Fe-S cluster-dependent enzyme aconitase. Further information regarding the effects of '882 has deepened our understanding of virulence regulation and demonstrates the potential for small-molecule modulation of Fe-S cluster assembly in S. aureus and other pathogens.
Copyright © 2016 Elsevier Ltd. All rights reserved.
0 Communities
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14 MeSH Terms
Bacillithiol has a role in Fe-S cluster biogenesis in Staphylococcus aureus.
Rosario-Cruz Z, Chahal HK, Mike LA, Skaar EP, Boyd JM
(2015) Mol Microbiol 98: 218-42
MeSH Terms: Aconitate Hydratase, Apoproteins, Bacterial Proteins, Cysteine, Glucosamine, Glutamate Synthase, Homeostasis, Iron, Iron-Sulfur Proteins, Oxidation-Reduction, Phenotype, Staphylococcus aureus, Sulfur
Show Abstract · Added February 8, 2016
Staphylococcus aureus does not produce the low-molecular-weight (LMW) thiol glutathione, but it does produce the LMW thiol bacillithiol (BSH). To better understand the roles that BSH plays in staphylococcal metabolism, we constructed and examined strains lacking BSH. Phenotypic analysis found that the BSH-deficient strains cultured either aerobically or anaerobically had growth defects that were alleviated by the addition of exogenous iron (Fe) or the amino acids leucine and isoleucine. The activities of the iron-sulfur (Fe-S) cluster-dependent enzymes LeuCD and IlvD, which are required for the biosynthesis of leucine and isoleucine, were decreased in strains lacking BSH. The BSH-deficient cells also had decreased aconitase and glutamate synthase activities, suggesting a general defect in Fe-S cluster biogenesis. The phenotypes of the BSH-deficient strains were exacerbated in strains lacking the Fe-S cluster carrier Nfu and partially suppressed by multicopy expression of either sufA or nfu, suggesting functional overlap between BSH and Fe-S carrier proteins. Biochemical analysis found that SufA bound and transferred Fe-S clusters to apo-aconitase, verifying that it serves as an Fe-S cluster carrier. The results presented are consistent with the hypothesis that BSH has roles in Fe homeostasis and the carriage of Fe-S clusters to apo-proteins in S. aureus.
© 2015 John Wiley & Sons Ltd.
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13 MeSH Terms
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
(2015) Mol Microbiol 95: 383-409
MeSH Terms: Aconitate Hydratase, Animals, DNA Damage, Disease Models, Animal, 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
Show Abstract · Added January 24, 2015
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.
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19 MeSH Terms
Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice.
Jones MK, Zhu E, Sarino EV, Padilla OR, Takahashi T, Shimizu T, Shirasawa T
(2011) Am J Physiol Gastrointest Liver Physiol 301: G537-46
MeSH Terms: Aconitate Hydratase, Animals, Apoptosis, Gastric Acid, Gastric Mucosa, Mice, Mice, Knockout, Mitochondria, Mitochondrial Proton-Translocating ATPases, Oxidative Phosphorylation, Oxidative Stress, Parietal Cells, Gastric, Superoxide Dismutase, Superoxides
Show Abstract · Added August 27, 2013
Mitochondrial superoxide dismutase (SOD2) prevents accumulation of the superoxide that arises as a consequence of oxidative phosphorylation. However, SOD2 is a target of oxidative/nitrosative inactivation, and reduced SOD2 activity has been demonstrated to contribute to portal hypertensive gastropathy. We investigated the consequences of gastric parietal cell-specific SOD2 deficiency on mitochondrial function and gastric injury susceptibility. Mice expressing Cre recombinase under control of the parietal cell Atpase4b gene promoter were crossed with mice harboring loxP sequences flanking the sod2 gene (SOD2 floxed mice). Cre-positive mice and Cre-negative littermates (controls) were used in studies of SOD2 expression, parietal cell function (ATP synthesis, acid secretion, and mitochondrial enzymatic activity), increased oxidative/nitrosative stress, and gastric susceptibility to acute injury. Parietal cell SOD2 deficiency was accompanied by a 20% (P < 0.05) reduction in total gastric SOD activity and a 93% (P < 0.001) reduction in gastric SOD2 activity. In SOD2-deficient mice, mitochondrial aconitase and ATP synthase activities were impaired by 36% (P < 0.0001) and 44% (P < 0.005), respectively. Gastric tissue ATP content was reduced by 34% (P < 0.002). Basal acid secretion and peak secretagogue (histamine)-induced acid secretion were reduced by 43% (P < 0.0001) and 40% (P < 0.0005), respectively. There was a fourfold (P < 0.02) increase in gastric mucosal apoptosis and 41% (P < 0.001) greater alcohol-induced gastric damage in the parietal cell SOD2-deficient mice. Our findings indicate that loss of parietal cell SOD2 leads to mitochondrial dysfunction, resulting in perturbed energy metabolism, impaired parietal cell function, and increased gastric mucosal oxidative stress. These alterations render the gastric mucosa significantly more susceptible to acute injury.
0 Communities
1 Members
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14 MeSH Terms
Enhanced hippocampal F2-isoprostane formation following kainate-induced seizures.
Patel M, Liang LP, Roberts LJ
(2001) J Neurochem 79: 1065-9
MeSH Terms: Aconitate Hydratase, Animals, Cell Count, Cell Death, Cell Survival, Excitatory Amino Acid Agonists, F2-Isoprostanes, Fumarate Hydratase, Hippocampus, Kainic Acid, Lipid Peroxidation, Male, Mitochondria, Rats, Rats, Sprague-Dawley, Seizures, Superoxides
Show Abstract · Added December 10, 2013
We attempted to obtain evidence for the occurrence of oxidant injury following seizure activity by measuring hippocampal F2-isoprostanes (F2-IsoPs), a reliable marker of free radical-induced lipid peroxidation. Formation of F2-IsoPs esterified in hippocampal phospholipids was correlated with hippocampal neuronal loss and mitochondrial aconitase inactivation, a marker of superoxide production in the kainate model. F2-IsoPs were measured in microdissected hippocampal CA1, CA3 and dentate gyrus (DG) regions at various times following kainate administration. Kainate produced a large increase in F2-IsoP levels in the highly vulnerable CA3 region 16 h post injection. The CA1 region showed small, but statistically insignificant increases in F2-IsoP levels. Interestingly, the DG, a region resistant to kainate-induced neuronal death also showed marked (2.5-5-fold) increases in F2-IsoP levels 8, 16, and 24 h post injection. The increases in F2-Isop levels in CA3 and DG were accompanied by inactivation of mitochondrial aconitase in these regions. This marked subregion-specific increase in F2-Isop following kainate administration suggests that oxidative lipid damage results from seizure activity and may play an important role in seizure-induced death of vulnerable neurons.
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17 MeSH Terms