scholarly journals Antagonistic Rgg Regulators Mediate Quorum Sensing via Competitive DNA Binding in Streptococcus pyogenes

mBio ◽  
2012 ◽  
Vol 3 (6) ◽  
Author(s):  
Breah LaSarre ◽  
Chaitanya Aggarwal ◽  
Michael J. Federle
Keyword(s):  
Dna Binding ◽  
Quorum Sensing ◽  
Streptococcus Pyogenes ◽  
Target Genes ◽  
Transcriptional Regulators ◽  
Content Type ◽  
Bacterial Physiology ◽  
Signaling Peptides ◽  
Direct Competition ◽  
Target Promoters

ABSTRACTRecent studies have established the fact that multiple members of the Rgg family of transcriptional regulators serve as key components of quorum sensing (QS) pathways that utilize peptides as intercellular signaling molecules. We previously described a novel QS system inStreptococcus pyogeneswhich utilizes two Rgg-family regulators (Rgg2 and Rgg3) that respond to neighboring signaling peptides (SHP2 and SHP3) to control gene expression and biofilm formation. We have shown that Rgg2 is a transcriptional activator of target genes, whereas Rgg3 represses expression of these genes, and that SHPs function to activate the QS system. The mechanisms by which Rgg proteins regulate both QS-dependent and QS-independent processes remain poorly defined; thus, we sought to further elucidate how Rgg2 and Rgg3 mediate gene regulation. Here we provide evidence thatS. pyogenesemploys a unique mechanism of direct competition between the antagonistic, peptide-responsive proteins Rgg2 and Rgg3 for binding at target promoters. The highly conserved, shared binding sites for Rgg2 and Rgg3 are located proximal to the −35 nucleotide in the target promoters, and the direct competition between the two regulators results in concentration-dependent, exclusive occupation of the target promoters that can be skewed in favor of Rgg2in vitroby the presence of SHP. These results suggest that exclusionary binding of target promoters by Rgg3 may prevent Rgg2 binding under SHP-limiting conditions, thereby preventing premature induction of the quorum sensing circuit.IMPORTANCERgg-family transcriptional regulators are widespread among low-G+C Gram-positive bacteria and in many cases contribute to bacterial physiology and virulence. Only recently was it discovered that several Rgg proteins function in cell-to-cell communication (quorum sensing [QS]) via direct interaction with signaling peptides. The mechanism(s) by which Rgg proteins mediate regulation is poorly understood, and further insight into Rgg function is anticipated to be of great importance for the understanding of both regulatory-network architecture and intercellular communication in Rgg-containing species. The results of this study on the Rgg2/3 QS circuit ofS. pyogenesdemonstrate that DNA binding of target promoters by the activator Rgg2 is directly inhibited by competitive binding by the repressor Rgg3, thereby preventing transcriptional activation of the target genes and premature induction of the QS circuit. This is a unique regulatory mechanism among Rgg proteins and other peptide-responsive QS regulators.

scholarly journals The Cyclic AMP Receptor Protein Regulates Quorum Sensing and Global Gene Expression in Yersinia pestis during Planktonic Growth and Growth in Biofilms

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Jeremy T. Ritzert ◽  
George Minasov ◽  
Ryan Embry ◽  
Matthew J. Schipma ◽  
Karla J. F. Satchell
Keyword(s):  
Gene Expression ◽  
Quorum Sensing ◽  
Carbon Source ◽  
Cyclic Amp ◽  
Yersinia Pestis ◽  
Carbon Sources ◽  
Transcriptional Regulator ◽  
Receptor Protein ◽  
Content Type ◽  
Bacterial Physiology

ABSTRACT Cyclic AMP (cAMP) receptor protein (Crp) is an important transcriptional regulator of Yersinia pestis. Expression of crp increases during pneumonic plague as the pathogen depletes glucose and forms large biofilms within lungs. To better understand control of Y. pestis Crp, we determined a 1.8-Å crystal structure of the protein-cAMP complex. We found that compared to Escherichia coli Crp, C helix amino acid substitutions in Y. pestis Crp did not impact the cAMP dependency of Crp to bind DNA promoters. To investigate Y. pestis Crp-regulated genes during plague pneumonia, we performed RNA sequencing on both wild-type and Δcrp mutant bacteria growing in planktonic and biofilm states in minimal media with glucose or glycerol. Y. pestis Crp was found to dramatically alter expression of hundreds of genes in a manner dependent upon carbon source and growth state. Gel shift assays confirmed direct regulation of the malT and ptsG promoters, and Crp was then linked to Y. pestis growth on maltose as a sole carbon source. Iron regulation genes ybtA and fyuA were found to be indirectly regulated by Crp. A new connection between carbon source and quorum sensing was revealed as Crp was found to regulate production of acyl-homoserine lactones (AHLs) through direct and indirect regulation of genes for AHL synthetases and receptors. AHLs were subsequently identified in the lungs of Y. pestis-infected mice when crp expression was highest in Y. pestis biofilms. Thus, in addition to the well-studied pla gene, other Crp-regulated genes likely have important functions during plague infection. IMPORTANCE Bacterial pathogens have evolved extensive signaling pathways to translate environmental signals into changes in gene expression. While Crp has long been appreciated for its role in regulating metabolism of carbon sources in many bacterial species, transcriptional profiling has revealed that this protein regulates many other aspects of bacterial physiology. The plague pathogen Y. pestis requires this global regulator to survive in blood, skin, and lungs. During disease progression, this organism adapts to changes within these niches. In addition to regulating genes for metabolism of nonglucose sugars, we found that Crp regulates genes for virulence, metal acquisition, and quorum sensing by direct or indirect mechanisms. Thus, this single transcriptional regulator, which responds to changes in available carbon sources, can regulate multiple critical behaviors for causing disease.

scholarly journals The Streptomyces filipinensis Gamma-Butyrolactone System Reveals Novel Clues for Understanding the Control of Secondary Metabolism

2020 ◽  
Vol 86 (18) ◽  
Author(s):  
Eva G. Barreales ◽  
Tamara D. Payero ◽  
Ester Jambrina ◽  
Jesús F. Aparicio
Keyword(s):  
Quorum Sensing ◽  
Secondary Metabolism ◽  
Target Genes ◽  
Antibiotic Production ◽  
The Other ◽  
Antimycin A ◽  
Dependent Manner ◽  
Biosynthetic Genes ◽  
Content Type ◽  
Communication Signals

ABSTRACT Streptomyces γ-butyrolactones (GBLs) are quorum sensing communication signals triggering antibiotic production. The GBL system of Streptomyces filipinensis, the producer of the antifungal agent filipin, has been investigated. Inactivation of sfbR (for S. filipinensis γ-butyrolactone receptor), a GBL receptor, resulted in a strong decrease in production of filipin, and deletion of sfbR2, a pseudo-receptor, boosted it, in agreement with lower and higher levels of transcription of filipin biosynthetic genes, respectively. It is noteworthy that none of the mutations affected growth or morphological development. While no ARE (autoregulatory element)-like sequences were found in the promoters of filipin genes, suggesting indirect control of production, five ARE sequences were found in five genes of the GBL cluster, whose transcription has been shown to be controlled by both S. filipinensis SfbR and SfbR2. In vitro binding of recombinant SfbR and SfbR2 to such sequences indicated that such control is direct. Transcription start points were identified by 5′ rapid amplification of cDNA ends, and precise binding regions were investigated by the use of DNase I protection studies. Binding of both regulators took place in the promoter of target genes and at the same sites. Information content analysis of protected sequences in target promoters yielded an 18-nucleotide consensus ARE sequence. Quantitative transcriptional analyses revealed that both regulators are self-regulated and that each represses the transcription of the other as well as that of the remaining target genes. Unlike other GBL receptor homologues, SfbR activates its own transcription whereas SfbR2 has a canonical autorepression profile. Additionally, SfbR2 was found here to bind the antifungal antimycin A as a way to modulate its DNA-binding activity. IMPORTANCE Streptomyces GBLs are important signaling molecules that trigger antibiotic production in a quorum sensing-dependent manner. We have characterized the GBL system from S. filipinensis, finding that two key players of this system, the GBL receptor and the pseudo-receptor, each counteracts the transcription of the other for the modulation of filipin production and that such control over antifungal production involves an indirect effect on the transcription of filipin biosynthetic genes. Additionally, the two regulators bind the same sites, are self-regulated, and repress the transcription of three other genes of the GBL cluster, including that encoding the GBL synthase. In contrast to all the GBL receptors known, SfbR activates its own synthesis. Moreover, the pseudo-receptor was identified as the receptor of antimycin A, thus extending the range of examples supporting the idea of signaling effects of antibiotics in Streptomyces. The intricate regulatory network depicted here should provide important clues for understanding the regulatory mechanism governing secondary metabolism.

scholarly journals A rhlI 5′ UTR-Derived sRNA Regulates RhlR-Dependent Quorum Sensing in Pseudomonas aeruginosa

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Maureen K. Thomason ◽  
Maya Voichek ◽  
Daniel Dar ◽  
Victoria Addis ◽  
David Fitzgerald ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Homoserine Lactone ◽  
Regulatory Elements ◽  
Content Type ◽  
Reading Frame ◽  
Bacterial Physiology ◽  
Small Regulatory Rna ◽  
Key Enzyme ◽  
Opportunistic Human Pathogen

ABSTRACT N-Acyl homoserine lactone (AHL) quorum sensing (QS) controls expression of over 200 genes in Pseudomonas aeruginosa. There are two AHL regulatory systems: the LasR-LasI circuit and the RhlR-RhlI system. We mapped transcription termination sites affected by AHL QS in P. aeruginosa, and in doing so we identified AHL-regulated small RNAs (sRNAs). Of interest, we noted that one particular sRNA was located within the rhlI locus. We found that rhlI, which encodes the enzyme that produces the AHL N-butanoyl-homoserine lactone (C4-HSL), is controlled by a 5′ untranslated region (UTR)-derived sRNA we name RhlS. We also identified an antisense RNA encoded opposite the beginning of the rhlI open reading frame, which we name asRhlS. RhlS accumulates as wild-type cells enter stationary phase and is required for the production of normal levels of C4-HSL through activation of rhlI translation. RhlS also directly posttranscriptionally regulates at least one other unlinked gene, fpvA. The asRhlS appears to be expressed at maximal levels during logarithmic growth, and we suggest RhlS may act antagonistically to the asRhlS to regulate rhlI translation. The rhlI-encoded sRNAs represent a novel aspect of RNA-mediated tuning of P. aeruginosa QS. IMPORTANCE The opportunistic human pathogen Pseudomonas aeruginosa possesses multiple quorum sensing systems that regulate and coordinate production of virulence factors and adaptation to different environments. Despite extensive research, the regulatory elements that play a role in this complex network are still not fully understood. By using several RNA sequencing techniques, we were able to identify a small regulatory RNA we named RhlS. RhlS increases translation of RhlI, a key enzyme in the quorum sensing pathway, and represses the fpvA mRNA encoding one of the siderophore pyoverdine receptors. Our results highlight a new regulatory layer of P. aeruginosa quorum sensing and contribute to the growing understanding of the role regulatory RNAs play in bacterial physiology.

scholarly journals Integration of Cyclic di-GMP and Quorum Sensing in the Control ofvpsTandaphAin Vibrio cholerae

2011 ◽  
Vol 193 (22) ◽  
pp. 6331-6341 ◽  
Author(s):  
Disha Srivastava ◽  
Rebecca C. Harris ◽  
Christopher M. Waters
Keyword(s):  
Quorum Sensing ◽  
Binding Site ◽  
Vibrio Cholerae ◽  
Biofilm Formation ◽  
Virulence Gene ◽  
Transcriptional Activator ◽  
Transcriptional Regulators ◽  
Content Type ◽  
Virulence Gene Expression ◽  
Signaling Systems

Vibrio choleraetransitions between aquatic environmental reservoirs and infection in the gastrointestinal tracts of human hosts. The second-messenger molecule cyclic di-GMP (c-di-GMP) and quorum sensing (QS) are important signaling systems that enableV. choleraeto alternate between these distinct environments by controlling biofilm formation and virulence factor expression. Here we identify a conserved regulatory mechanism inV. choleraethat integrates c-di-GMP and QS to control the expression of two transcriptional regulators:aphA, an activator of virulence gene expression and an important regulator of the quorum-sensing pathway, andvpsT, a transcriptional activator that induces biofilm formation. Surprisingly,aphAexpression was induced by c-di-GMP. Activation of bothaphAandvpsTby c-di-GMP requires the transcriptional activator VpsR, which binds to c-di-GMP. The VpsR binding site at each of these promoters overlaps with the binding site of HapR, the master QS regulator at high cell densities. Our results suggest thatV. choleraecombines information conveyed by QS and c-di-GMP to appropriately respond and adapt to divergent environments by modulating the expression of key transcriptional regulators.

scholarly journals Structure-Based Functional Characterization of Repressor of Toxin (Rot), a Central Regulator of Staphylococcus aureus Virulence

2014 ◽  
Vol 197 (1) ◽  
pp. 188-200 ◽  
Author(s):  
April Killikelly ◽  
Meredith A. Benson ◽  
Elizabeth A. Ohneck ◽  
Jared M. Sampson ◽  
Jean Jakoncic ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dna Binding ◽  
Virulence Factors ◽  
Regulatory Networks ◽  
Functional Characterization ◽  
Site Directed Mutagenesis ◽  
Binding Motif ◽  
Content Type ◽  
Specific Effects ◽  
Target Promoters

Staphylococcus aureusis responsible for a large number of diverse infections worldwide. In order to support its pathogenic lifestyle,S. aureushas to regulate the expression of virulence factors in a coordinated fashion. One of the central regulators of theS. aureusvirulence regulatory networks is the transcription factor repressor of toxin (Rot). Rot plays a key role in regulatingS. aureusvirulence through activation or repression of promoters that control expression of a large number of critical virulence factors. However, the mechanism by which Rot mediates gene regulation has remained elusive. Here, we have determined the crystal structure of Rot and used this information to probe the contribution made by specific residues to Rot function. Rot was found to form a dimer, with each monomer harboring a winged helix-turn-helix (WHTH) DNA-binding motif. Despite an overall acidic pI, the asymmetric electrostatic charge profile suggests that Rot can orient the WHTH domain to bind DNA. Structure-based site-directed mutagenesis studies demonstrated that R91, at the tip of the wing, plays an important role in DNA binding, likely through interaction with the minor groove. We also found that Y66, predicted to bind within the major groove, contributes to Rot interaction with target promoters. Evaluation of Rot binding to different activated and repressed promoters revealed that certain mutations on Rot exhibit promoter-specific effects, suggesting for the first time that Rot differentially interacts with target promoters. This work provides insight into a precise mechanism by which Rot controls virulence factor regulation inS. aureus.

scholarly journals A Region of Bacillus subtilis CodY Protein Required for Interaction with DNA

2005 ◽  
Vol 187 (12) ◽  
pp. 4127-4139 ◽  
Author(s):  
Pascale Joseph ◽  
Manoja Ratnayake-Lecamwasam ◽  
Abraham L. Sonenshein
Keyword(s):  
Bacillus Subtilis ◽  
Dna Binding ◽  
Dna Recognition ◽  
Transcriptional Regulators ◽  
Site Directed Mutagenesis ◽  
Regulation Of Transcription ◽  
Gram Positive Bacteria ◽  
Target Promoters

ABSTRACT Bacillus subtilis CodY protein is the best-studied member of a novel family of global transcriptional regulators found ubiquitously in low-G+C gram-positive bacteria. As for many DNA-binding proteins, CodY appears to have a helix-turn-helix (HTH) motif thought to be critical for interaction with DNA. This putative HTH motif was found to be highly conserved in the CodY homologs. Site-directed mutagenesis was used to identify amino acids within this motif that are important for DNA recognition and binding. The effects of each mutation on DNA binding in vitro and on the regulation of transcription in vivo from two target promoters were tested. Each of the mutations had similar effects on binding to the two promoters in vitro, but some mutations had differential effects in vivo.

scholarly journals Dissection of Combinatorial Control by the Met4 Transcriptional Complex

2010 ◽  
Vol 21 (3) ◽  
pp. 456-469 ◽  
Author(s):  
Traci A. Lee ◽  
Paul Jorgensen ◽  
Andrew L. Bognar ◽  
Caroline Peyraud ◽  
Dominique Thomas ◽  
...  
Keyword(s):  
Dna Binding ◽  
Metabolic Network ◽  
Target Genes ◽  
A Genome ◽  
Wide Scale ◽  
Combinatorial System ◽  
Transcriptional Complex ◽  
Differential Transcription ◽  
Target Promoters

Met4 is the transcriptional activator of the sulfur metabolic network in Saccharomyces cerevisiae. Lacking DNA-binding ability, Met4 must interact with proteins called Met4 cofactors to target promoters for transcription. Two types of DNA-binding cofactors (Cbf1 and Met31/Met32) recruit Met4 to promoters and one cofactor (Met28) stabilizes the DNA-bound Met4 complexes. To dissect this combinatorial system, we systematically deleted each category of cofactor(s) and analyzed Met4-activated transcription on a genome-wide scale. We defined a core regulon for Met4, consisting of 45 target genes. Deletion of both Met31 and Met32 eliminated activation of the core regulon, whereas loss of Met28 or Cbf1 interfered with only a subset of targets that map to distinct sectors of the sulfur metabolic network. These transcriptional dependencies roughly correlated with the presence of Cbf1 promoter motifs. Quantitative analysis of in vivo promoter binding properties indicated varying levels of cooperativity and interdependency exists between members of this combinatorial system. Cbf1 was the only cofactor to remain fully bound to target promoters under all conditions, whereas other factors exhibited different degrees of regulated binding in a promoter-specific fashion. Taken together, Met4 cofactors use a variety of mechanisms to allow differential transcription of target genes in response to various cues.

scholarly journals Signal Biosynthesis Inhibition with Ambuic Acid as a Strategy To Target Antibiotic-Resistant Infections

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Daniel A. Todd ◽  
Corey P. Parlet ◽  
Heidi A. Crosby ◽  
Cheryl L. Malone ◽  
Kristopher P. Heilmann ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Bacterial Infections ◽  
Bacterial Pathogens ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Lead Compounds ◽  
Major Interest ◽  
Signaling Peptides

ABSTRACT There has been major interest by the scientific community in antivirulence approaches against bacterial infections. However, partly due to a lack of viable lead compounds, antivirulence therapeutics have yet to reach the clinic. Here we investigate the development of an antivirulence lead targeting quorum sensing signal biosynthesis, a process that is conserved in Gram-positive bacterial pathogens. Some preliminary studies suggest that the small molecule ambuic acid is a signal biosynthesis inhibitor. To confirm this, we constructed a methicillin-resistant Staphylococcus aureus (MRSA) strain that decouples autoinducing peptide (AIP) production from regulation and demonstrate that AIP production is inhibited in this mutant. Quantitative mass spectrometric measurements show that ambuic acid inhibits signal biosynthesis (50% inhibitory concentration [IC50] of 2.5 ± 0.1 μM) against a clinically relevant USA300 MRSA strain. Quantitative real-time PCR confirms that this compound selectively targets the quorum sensing regulon. We show that a 5-μg dose of ambuic acid reduces MRSA-induced abscess formation in a mouse model and verify its quorum sensing inhibitory activity in vivo. Finally, we employed mass spectrometry to identify or confirm the structure of quorum sensing signaling peptides in three strains each of S. aureus and Staphylococcus epidermidis and single strains of Enterococcus faecalis, Listeria monocytogenes, Staphylococcus saprophyticus, and Staphylococcus lugdunensis. By measuring AIP production by these strains, we show that ambuic acid possesses broad-spectrum efficacy against multiple Gram-positive bacterial pathogens but does not inhibit quorum sensing in some commensal bacteria. Collectively, these findings demonstrate the promise of ambuic acid as a lead for the development of antivirulence therapeutics.

scholarly journals Multiple and Overlapping Functions of Quorum Sensing Proteins for Cell Specialization in Bacillus Species

2020 ◽  
Vol 202 (10) ◽  
Author(s):  
Abel Verdugo-Fuentes ◽  
Gabriela Gastélum ◽  
Jorge Rocha ◽  
Mayra de la Torre
Keyword(s):  
Quorum Sensing ◽  
Bacillus Species ◽  
Bacterial Populations ◽  
Content Type ◽  
Collective Behaviors ◽  
Gram Positive Bacteria ◽  
Signaling Peptides ◽  
Moonlighting Proteins ◽  
Sporulation Initiation ◽  
Cell Specialization

ABSTRACT In bacterial populations, quorum sensing (QS) systems participate in the regulation of specialization processes and regulate collective behaviors that mediate interactions and allow survival of the species. In Gram-positive bacteria, QS systems of the RRNPP family (Rgg, Rap, NprR, PlcR, and PrgX) consist of intracellular receptors and their cognate signaling peptides. Two of these receptors, Rap and NprR, have regained attention in Bacillus subtilis and the Bacillus cereus group. Some Rap proteins, such as RapH and Rap60, are multifunctional and/or redundant in function, linking the specialization processes of sporulation and competence, as well as global expression changes in the transition phase in B. subtilis. NprR, an evolutionary intermediate between Rap and RRNPP transcriptional activators, is a bifunctional regulator that modulates sporulation initiation and activates nutrient scavenging genes. In this review, we discuss how these receptors switch between functions and connect distinct signaling pathways. Based on structural evidence, we propose that RapH and Rap60 should be considered moonlighting proteins. Additionally, we analyze an evolutionary and ecological perspective to understand the multifunctionality and functional redundancy of these regulators in both Bacillus spp. and non-Bacillus Firmicutes. Understanding the mechanistic, structural, ecological, and evolutionary basis for the multifunctionality and redundancy of these QS systems is a key step for achieving the development of innovative technologies for health and agriculture.

scholarly journals Role of Glutathione in Buffering Excess Intracellular Copper in Streptococcus pyogenes

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Louisa J. Stewart ◽  
Cheryl-lynn Y. Ong ◽  
May M. Zhang ◽  
Stephan Brouwer ◽  
Liam McIntyre ◽  
...  
Keyword(s):  
Streptococcus Pyogenes ◽  
Metal Binding ◽  
Metal Ion ◽  
Physiological Role ◽  
Metal Availability ◽  
Content Type ◽  
Bacterial Physiology ◽  
Group A

ABSTRACT Copper (Cu) is an essential metal for bacterial physiology but in excess it is bacteriotoxic. To limit Cu levels in the cytoplasm, most bacteria possess a transcriptionally responsive system for Cu export. In the Gram-positive human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]), this system is encoded by the copYAZ operon. This study demonstrates that although the site of GAS infection represents a Cu-rich environment, inactivation of the copA Cu efflux gene does not reduce virulence in a mouse model of invasive disease. In vitro, Cu treatment leads to multiple observable phenotypes, including defects in growth and viability, decreased fermentation, inhibition of glyceraldehyde-3-phosphate dehydrogenase (GapA) activity, and misregulation of metal homeostasis, likely as a consequence of mismetalation of noncognate metal-binding sites by Cu. Surprisingly, the onset of these effects is delayed by ∼4 h even though expression of copZ is upregulated immediately upon exposure to Cu. Further biochemical investigations show that the onset of all phenotypes coincides with depletion of intracellular glutathione (GSH). Supplementation with extracellular GSH replenishes the intracellular pool of this thiol and suppresses all the observable effects of Cu treatment. These results indicate that GSH buffers excess intracellular Cu when the transcriptionally responsive Cu export system is overwhelmed. Thus, while the copYAZ operon is responsible for Cu homeostasis, GSH has a role in Cu tolerance and allows bacteria to maintain metabolism even in the presence of an excess of this metal ion. IMPORTANCE The control of intracellular metal availability is fundamental to bacterial physiology. In the case of copper (Cu), it has been established that rising intracellular Cu levels eventually fill the metal-sensing site of the endogenous Cu-sensing transcriptional regulator, which in turn induces transcription of a copper export pump. This response caps intracellular Cu availability below a well-defined threshold and prevents Cu toxicity. Glutathione, abundant in many bacteria, is known to bind Cu and has long been assumed to contribute to bacterial Cu handling. However, there is some ambiguity since neither its biosynthesis nor uptake is Cu-regulated. Furthermore, there is little experimental support for this physiological role of glutathione beyond measuring growth of glutathione-deficient mutants in the presence of Cu. Our work with group A Streptococcus provides new evidence that glutathione increases the threshold of intracellular Cu availability that can be tolerated by bacteria and thus advances fundamental understanding of bacterial Cu handling.

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