Physiological roles of bacillithiol in intracellular metal processing

Rosario-Cruz, Zuelay; Boyd, Jeffrey M.

doi:10.1007/s00294-015-0511-0

Cited by 29 publications

(21 citation statements)

References 46 publications

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“…Prominent among these were SufCD, which are required to synthesize iron-sulfur (Fe-S) cofactors (52). S. aureus strains unable to properly process Fe-S proteins into their mature forms display global shifts in carbon flux and metabolic defects (47,51,(53)(54)(55). Consistent with these studies, we found that a clpC mutant had deficient respiratory growth.…”

Section: Discussionsupporting

confidence: 77%

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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Section: Discussionsupporting

confidence: 77%

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

et al. 2019

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“…We also determined that similar to what has been reported for Bacillus subtilis (44), T. thermophilus BSH mutants were more sensitive to Zn(II) than the WT strain (data not shown). This information suggests that BSH has a general role in metal ion tolerance and/or buffering (45). Thermus mer operons are not the only ones that contain thiol-related genes; some alphaproteobacterial mer operons include gor, a glutathione reductase gene.…”

Section: Discussionmentioning

confidence: 99%

Low-Molecular-Weight Thiols and Thioredoxins Are Important Players in Hg(II) Resistance in Thermus thermophilus HB27

Norambuena

Wang

Hanson

et al. 2018

Appl Environ Microbiol

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Mercury (Hg), one of the most toxic and widely distributed heavy metals, has a high affinity for thiol groups. Thiol groups reduce and sequester Hg. Therefore, low molecular weight and protein thiols may be important cell components used in Hg resistance. To date, the role of low molecular weight thiols in Hg-detoxification remains understudied. The mercury resistance () operon of suggests an evolutionary link between Hg(II) resistance and low molecular weight thiol metabolism. This operon encodes for an enzyme involved in methionine biosynthesis, Oah. Challenge with Hg(II) resulted in increased expression of genes involved in the biosynthesis of multiple low molecular weight thiols (cysteine, homocysteine, and bacillithiol), as well as the thioredoxin system. Phenotypic analysis of gene replacement mutants indicated that Oah contributes to Hg resistance under sulfur limiting conditions, and strains lacking bacillithiol and/or thioredoxins are more sensitive to Hg(II) than the wild type. Growth in presence of either a thiol oxidizing agent or a thiol alkylating agent increased sensitivity to Hg(II). Furthermore, exposure to 3 μM Hg(II) consumed all intracellular reduced bacillithiol and cysteine. Database searches indicate that is present in all spp. operons. The presence of a thiol related gene was also detected in some alphaprotobacterial operons, in which a glutathione reductase gene was present, supporting the role of thiols in Hg(II) detoxification. These results have led to a working model in which LMW thiols act as Hg(II) buffering agents while Hg is reduced by MerA.The survival of microorganisms in presence of toxic metals is central to life's sustainability. The affinity of thiol groups to toxic heavy metals drives microbe-metal interactions and modulate metal toxicity. Mercury detoxification () genes likely originated early in microbial evolution among geothermal environments. Little is known about how systems interact with cellular thiol systems. spp. possess a simple operon in which a low molecular weight thiol biosynthesis gene is present, along with and In this study, we present experimental evidence for the role of thiol systems in mercury resistance. Our data suggest that in thiolated compounds may function side-by-side with genes to detoxify mercury. Thus, thiol systems function in consort with-mediated resistance to mercury, suggesting exciting new questions for future research.

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“…SufA and Nfu function as Fe-S cluster carriers in S. aureus (7,18). Genetic evidence suggests that SufT and bacillithiol also have roles in the maturation of Fe-S proteins (18)(19)(20).…”

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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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Physiological roles of bacillithiol in intracellular metal processing

Cited by 29 publications

References 46 publications

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

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

Low-Molecular-Weight Thiols and Thioredoxins Are Important Players in Hg(II) Resistance in Thermus thermophilus HB27

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

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