The Staphylococcus aureus SrrAB Regulatory System Modulates Hydrogen Peroxide Resistance Factors, Which Imparts Protection to Aconitase during Aerobic Growth

Mashruwala, Ameya A.; Boyd, Jeffrey M.

doi:10.1371/journal.pone.0170283

Cited by 50 publications

(30 citation statements)

References 97 publications

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“…aureus increases the transcription of genes necessary to metabolize reactive oxygen species (ROS) when cultured under high aeration, suggesting that endogenous ROS accumulates under these growth conditions (33). Consequently, S. aureus strains deficient in the maturation of Fe-S proteins or scavenging endogenously produced ROS display severe defects in AcnA activity when the dioxygen tension is increased (19).…”

Section: Resultsmentioning

confidence: 99%

The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils

et al. 2017

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Staphylococcus aureus remains a causative agent for morbidity and mortality worldwide. This is in part a result of antimicrobial resistance, highlighting the need to uncover novel antibiotic targets and to discover new therapeutic agents. In the present study, we explored the possibility that iron-sulfur (Fe-S) cluster synthesis is a viable antimicrobial target. RNA interference studies established that Suf (sulfur mobilization)-dependent Fe-S cluster synthesis is essential in S. aureus. We found that sufCDSUB were cotranscribed and that suf transcription was positively influenced by sigma factor B. We characterized an S. aureus strain that contained a transposon inserted in the intergenic space between sufC and sufD (sufD*), resulting in decreased transcription of sufSUB. Consistent with the transcriptional data, the sufD* strain had multiple phenotypes associated with impaired Fe-S protein maturation. They included decreased activities of Fe-S cluster-dependent enzymes, decreased growth in media lacking metabolites that require Fe-S proteins for synthesis, and decreased flux through the tricarboxylic acid (TCA) cycle. Decreased Fe-S cluster synthesis resulted in sensitivity to reactive oxygen and reactive nitrogen species, as well as increased DNA damage and impaired DNA repair. The sufD* strain also exhibited perturbed intracellular nonchelated Fe pools. Importantly, the sufD* strain did not exhibit altered exoprotein production or altered biofilm formation, but it was attenuated for survival upon challenge by human polymorphonuclear leukocytes. The results presented are consistent with the hypothesis that Fe-S cluster synthesis is a viable target for antimicrobial development.KEYWORDS iron, sulfur, cluster, Staphylococcus aureus, Suf, neutrophil S taphylococcus aureus is a human commensal that causes morbidity and mortality worldwide. While it is responsible for low-morbidity maladies, such as folliculitis, it is also capable of causing fatal afflictions, such as endocarditis, bacteremia, and toxic shock syndrome (1, 2). Bacterial antibiotic resistance continues to increase and to be problematic. Infections caused by antibiotic-resistant S. aureus result in increased mortality, increased stress on the health care system, and an increased financial burden (3, 4). Current FDA-approved antibacterials target a limited number of metabolic processes (5). Developing antibacterials that target alternate processes would expand treatment options and aid in multidrug therapy. These facts highlight the need for

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Section: Resultsmentioning

confidence: 99%

The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils

et al. 2017

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“…Presumably, the Δ ytfE strain is sensitive to other antimicrobial compounds generated within host tissues, possibly by the generation of a variety of reactive nitrogen species (RNS) as a consequence of NO reaction with reactive oxygen species (ROS) or other compounds. Upregulation of ytfE following hydrogen peroxide-mediated damage of Staphylococcus aureus indicates that YtfE may play a broad role in repair, instead of just a response to nitrogen stress (44, 45). Additional studies in E. coli also suggest that YtfE repairs Fe-S cluster proteins damaged by hydrogen peroxide (13, 46-49).…”

Section: Discussionmentioning

confidence: 99%

Iron-sulfur cluster repair contributes to Y. pseudotuberculosis survival within deep tissues

Davis

Krupp

Clark

et al. 2019

Preprint

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Iron-sulfur cluster repair contributes to Y. pseudotuberculosis survival within deep tissues. 1 2 3 Running title: Iron-sulfur cluster repair during Y. pseudotuberculosis infection 4 5 6 7 Abstract 24To successfully colonize host tissues, bacteria must respond to and detoxify many different host-25 derived antimicrobial compounds, such as nitric oxide (NO). NO can directly kill bacteria, 26 primarily through attack on iron-sulfur (Fe-S) cluster-containing proteins. NO detoxification 27 plays an important role in promoting bacterial survival, but it remains unclear if repair of Fe-S 28 clusters is also important for bacterial survival within host tissues. Here we show that the Fe-S 29 cluster repair protein, YtfE, contributes to the survival of Y. pseudotuberculosis within the spleen 30 following nitrosative stress. Y. pseudotuberculosis forms clustered centers of replicating bacteria 31 within deep tissues, where peripheral bacteria express the NO-detoxifying gene, hmp. ytfE 32 expression also occurred specifically within peripheral cells at the edges of microcolonies. In the 33 absence of ytfE, the area of microcolonies was significantly smaller than WT, consistent with 34 ytfE contributing to the survival of peripheral cells. The loss of ytfE did not alter the ability of 35 cells to detoxify NO, which occurred within peripheral cells in both WT and ∆ytfE 36 microcolonies. In the absence of NO-detoxifying activity by hmp, NO diffused across ∆ytfE 37 microcolonies, and there was a significant decrease in the area of microcolonies lacking ytfE, 38indicating that ytfE also contributes to bacterial survival in the absence of NO detoxification. 39These results indicate a role for Fe-S cluster repair in the survival of Y. pseudotuberculosis 40 within the spleen, and suggest that extracellular bacteria may rely on this pathway for survival 41 within host tissues. 42

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“…RNA extractions and real-time quantitative PCR. The abundances of RNAs were determined using a previously described cDNA library (35,53). Briefly, cells were cultured in capped microcentrifuge tubes at a headspace-to-volume (H/V) ratio of 0.…”

Section: Methodsmentioning

confidence: 99%

“…ClpCP is required for optimal growth in a medium that only supports respiratory growth. SrrAB regulates aerobic respiration, and the data presented suggested that a ΔclpC strain may be deficient in oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity (35,36). This prompted us to test the hypothesis that ClpC positively influences respiratory growth.…”

Section: Figmentioning

confidence: 99%

“…The transcript levels for clpC were examined in the WT and ΔsrrAB strains following fermentative growth. Transcript levels for spa and cydB, which are negatively and positively modulated by SrrAB, were assessed as controls (33,35). Transcript levels were examined instead of transcriptional activity using the reporter constructs, since the folding of GFP is impaired in the absence of oxygen (50).…”

Section: Figmentioning

confidence: 99%

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The ClpCP Complex Modulates Respiratory Metabolism in Staphylococcus aureus and Is Regulated in a SrrAB-Dependent Manner

et al. 2019

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The staphylococcal respiratory regulator (SrrAB) modulates energy metabolism in Staphylococcus aureus. Studies have suggested that regulated protein catabolism facilitates energy homeostasis. Regulated proteolysis in S. aureus is achieved through protein complexes composed of a peptidase (ClpQ or ClpP) in association with an AAA ϩ family ATPase (typically, ClpC or ClpX). In the present report, we tested the hypothesis that SrrAB regulates a Clp complex to facilitate energy homeostasis in S. aureus. Strains deficient in one or more Clp complexes were attenuated for growth in the presence of puromycin, which causes enrichment of misfolded proteins. A ΔsrrAB strain had increased sensitivity to puromycin. Epistasis experiments suggested that the puromycin sensitivity phenotype of the ΔsrrAB strain was a result of decreased ClpC activity. Consistent with this, transcriptional activity of clpC was decreased in the ΔsrrAB mutant, and overexpression of clpC suppressed the puromycin sensitivity of the ΔsrrAB strain. We also found that ClpC positively influenced respiration and that it did so upon association with ClpP. In contrast, ClpC limited fermentative growth, while ClpP was required for optimal fermentative growth. Metabolomics studies demonstrated that intracellular metabolic profiles of the ΔclpC and ΔsrrAB mutants were distinct from those of the wild-type strain, supporting the notion that both ClpC and SrrAB affect central metabolism. We propose a model wherein SrrAB regulates energy homeostasis, in part, via modulation of regulated proteolysis. IMPORTANCE Oxygen is used as a substrate to derive energy by the bacterial pathogen Staphylococcus aureus during infection; however, S. aureus can also grow fermentatively in the absence of oxygen. To successfully cause infection, S. aureus must tailor its metabolism to take advantage of respiratory activity. Different proteins are required for growth in the presence or absence of oxygen; therefore, when cells transition between these conditions, several proteins would be expected to become unnecessary. In this report, we show that regulated proteolysis is used to modulate energy metabolism in S. aureus. We report that the ClpCP protein complex is involved in specifically modulating aerobic respiratory growth but is dispensable for fermentative growth.

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The Staphylococcus aureus SrrAB Regulatory System Modulates Hydrogen Peroxide Resistance Factors, Which Imparts Protection to Aconitase during Aerobic Growth

Cited by 50 publications

References 97 publications

The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils

The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils

Iron-sulfur cluster repair contributes to Y. pseudotuberculosis survival within deep tissues

The ClpCP Complex Modulates Respiratory Metabolism in Staphylococcus aureus and Is Regulated in a SrrAB-Dependent Manner

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