Streptococcus pneumoniae Uses Glutathione To Defend against Oxidative Stress and Metal Ion Toxicity

Potter, Adam J.; Trappetti, Claudia; Paton, James C.

doi:10.1128/jb.01393-12

Cited by 102 publications

(109 citation statements)

References 51 publications

(51 reference statements)

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“…GSH has been shown to exert a major protective effect toward oxidative stress and acid stress, as well as the toxicity of arsenite, copper, and other heavy metal ions (14)(15)(16)(17)(18). When Streptococcus pneumoniae was allowed to take up GSH from the environment, it became more resistant to copper but also to the non-redox-active heavy metals cadmium and zinc (19). The latter observations hint at additional GSH-dependent detoxification processes that are not linked to oxidative stress.…”

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confidence: 69%

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Mechanism of Attenuation of Uranyl Toxicity by Glutathione in Lactococcus lactis

Obeid

Oertel

Solioz

et al. 2016

Appl Environ Microbiol

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b ABSTRACTBoth prokaryotic and eukaryotic organisms possess mechanisms for the detoxification of heavy metals, and these mechanisms are found among distantly related species. We investigated the role of intracellular glutathione (GSH), which, in a large number of taxa, plays a role in protection against the toxicity of common heavy metals. Anaerobically grown Lactococcus lactis containing an inducible GSH synthesis pathway was used as a model organism. Its physiological condition allowed study of putative GSH-dependent uranyl detoxification mechanisms without interference from additional reactive oxygen species. By microcalorimetric measurements of metabolic heat during cultivation, it was shown that intracellular GSH attenuates the toxicity of uranium at a concentration in the range of 10 to 150 M. In this concentration range, no effect was observed with copper, which was used as a reference for redox metal toxicity. At higher copper concentrations, GSH aggravated metal toxicity. Isothermal titration calorimetry revealed the endothermic binding of U(VI) to the carboxyl group(s) of GSH rather than to the reducing thiol group involved in copper interactions. The data indicate that the primary detoxifying mechanism is the intracellular sequestration of carboxyl-coordinated U(VI) into an insoluble complex with GSH. The opposite effects on uranyl and on copper toxicity can be related to the difference in coordination chemistry of the respective metal-GSH complexes, which cause distinct growth phase-specific effects on enzyme-metal interactions. IMPORTANCEUnderstanding microbial metal resistance is of particular importance for bioremediation, where microorganisms are employed for the removal of heavy metals from the environment. This strategy is increasingly being considered for uranium. However, little is known about the molecular mechanisms of uranyl detoxification. Existing studies of different taxa show little systematics but hint at a role of glutathione (GSH). Previous work could not unequivocally demonstrate a GSH function in decreasing the presumed uranyl-induced oxidative stress, nor could a redox-independent detoxifying action of GSH be identified. Combining metabolic calorimetry with cell number-based assays and genetics analysis enables a novel and general approach to quantify toxicity and relate it to molecular mechanisms. The results show that GSH-expressing microorganisms appear advantageous for uranyl bioremediation.T he natural abundance of uranium and the increasing health risks that originate from its anthropogenic release to the environment have generated a high demand for understanding the molecular mechanisms of uranium toxicity. Its radiotoxicity is of minor ecological relevance compared to its toxicity due to chemical interference with metabolism (1, 2). The latter is caused mostly by the displacement of Ca 2ϩ and Mg 2ϩ from functionally important binding sites in enzymes (3). The water-soluble uranyl cation UO 2 2ϩ is the most commonly found contaminant, which contains uranium in its highest ...

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confidence: 69%

“…Gram-negative organisms (18,19). However, under the anaerobic conditions employed here, GSH renders L. lactis more sensitive to copper, particularly during the first phase of exponential growth.…”

Section: Discussionmentioning

confidence: 90%

Mechanism of Attenuation of Uranyl Toxicity by Glutathione in Lactococcus lactis

Obeid

Oertel

Solioz

et al. 2016

Appl Environ Microbiol

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“…S. pyogenes is not known to produce siderophores and does not appear to have genes encoding homologues of siderophore production systems (68)(69)(70). S. pyogenes does not appear to synthesize GSH but, similar to other streptococcal species, may obtain it from the local environment (71,72). Additional studies on the potential involvement of GSH in the protective anticopper response of S. pyogenes are clearly merited.…”

Section: Figmentioning

confidence: 99%

Copper Tolerance and Characterization of a Copper-Responsive Operon, copYAZ , in an M1T1 Clinical Strain of Streptococcus pyogenes

et al. 2015

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Infection with Streptococcus pyogenes is associated with a breadth of clinical manifestations ranging from mild pharyngitis to severe necrotizing fasciitis. Elevated levels of intracellular copper are highly toxic to this bacterium, and thus, the microbe must tightly regulate the level of this metal ion by one or more mechanisms, which have, to date, not been clearly defined. In this study, we have identified two virulence mechanisms by which S. pyogenes protects itself against copper toxicity. We defined a set of putative genes, copY (for a regulator), copA (for a P1-type ATPase), and copZ (for a copper chaperone), whose expression is regulated by copper. Our results indicate that these genes are highly conserved among a range of clinical S. pyogenes isolates. The copY, copA, and copZ genes are induced by copper and are transcribed as a single unit. Heterologous expression assays revealed that S. pyogenes CopA can confer copper tolerance in a copper-sensitive Escherichia coli mutant by preventing the accumulation of toxic levels of copper, a finding that is consistent with a role for CopA in copper export. Evaluation of the effect of copper stress on S. pyogenes in a planktonic or biofilm state revealed that biofilms may aid in protection during initial exposure to copper. However, copper stress appears to prevent the shift from the planktonic to the biofilm state. Therefore, our results indicate that S. pyogenes may use several virulence mechanisms, including altered gene expression and a transition to and from planktonic and biofilm states, to promote survival during copper stress. IMPORTANCEBacterial pathogens encounter multiple stressors at the host-pathogen interface. This study evaluates a virulence mechanism(s) utilized by S. pyogenes to combat copper at sites of infection. A better understanding of pathogen tolerance to stressors such as copper is necessary to determine how host-pathogen interactions impact bacterial survival during infections. These insights may lead to the identification of novel therapeutic targets that can be used to address antibiotic resistance.

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“…GSH is the most abundant intracellular thiol present in eukaryotes. Its presence in prokaryotes has so far been described in cyanobacteria, proteobacteria, and some Gram-positive bacteria, such as Streptococcus pneumoniae (29) and Lactobacillus lactis (30). GSH protects bacteria against various physiological insults, such as ROS, osmotic stress, and toxic metal ions (31,32).…”

Section: Fig 3 Effects Of H 2 S On Intracellular Sulfide Levels and Gmentioning

confidence: 99%

Reduced Glutathione Mediates Resistance to H ₂ S Toxicity in Oral Streptococci

Ooi

Tan

2016

Appl Environ Microbiol

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Periodontal disease is associated with changes in the composition of the oral microflora, where health-associated oral streptococci decrease while Gram-negative anaerobes predominate in disease. A key feature of periodontal disease-associated anaerobes is their ability to produce hydrogen sulfide (H 2 S) abundantly as a by-product of anaerobic metabolism. So far, H 2 S has been reported to be either cytoprotective or cytotoxic by modulating bacterial antioxidant defense systems. Although oral anaerobes produce large amounts of H 2 S, the potential effects of H 2 S on oral streptococci are currently unknown. The aim of this study was to determine the effects of H 2 S on the survival and biofilm formation of oral streptococci. The growth and biofilm formation of Streptococcus mitis and Streptococcus oralis were inhibited by H 2 S. However, H 2 S did not significantly affect the growth of Streptococcus gordonii or Streptococcus sanguinis. The differential susceptibility of oral streptococci to H 2 S was attributed to differences in the intracellular concentrations of reduced glutathione (GSH). In the absence of GSH, H 2 S elicited its toxicity through an iron-dependent mechanism. Collectively, our results showed that H 2 S exerts antimicrobial effects on certain oral streptococci, potentially contributing to the decrease in health-associated plaque microflora.

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Streptococcus pneumoniae Uses Glutathione To Defend against Oxidative Stress and Metal Ion Toxicity

Cited by 102 publications

References 51 publications

Mechanism of Attenuation of Uranyl Toxicity by Glutathione in Lactococcus lactis

Mechanism of Attenuation of Uranyl Toxicity by Glutathione in Lactococcus lactis

Copper Tolerance and Characterization of a Copper-Responsive Operon, copYAZ , in an M1T1 Clinical Strain of Streptococcus pyogenes

Reduced Glutathione Mediates Resistance to H ₂ S Toxicity in Oral Streptococci

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Streptococcus pneumoniae Uses Glutathione To Defend against Oxidative Stress and Metal Ion Toxicity

Cited by 102 publications

References 51 publications

Mechanism of Attenuation of Uranyl Toxicity by Glutathione in Lactococcus lactis

Mechanism of Attenuation of Uranyl Toxicity by Glutathione in Lactococcus lactis

Copper Tolerance and Characterization of a Copper-Responsive Operon, copYAZ , in an M1T1 Clinical Strain of Streptococcus pyogenes

Reduced Glutathione Mediates Resistance to H 2 S Toxicity in Oral Streptococci

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Reduced Glutathione Mediates Resistance to H ₂ S Toxicity in Oral Streptococci