Molecular characterization of the copper transport system in Staphylococcus aureus

Sitthisak, Sutthirat; Knutsson, Lawrence; Webb, James W.; Jayaswal, Radheshyam K.

doi:10.1099/mic.0.2007/009860-0

Cited by 64 publications

(77 citation statements)

References 41 publications

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“…tumefaciens copA encodes a putative protein of 862 amino acid residues with a theoretical molecular mass of 90.1 kDa. The deduced A. tumefaciens CopA amino acid sequence shares high levels of identity to other bacterial Cu ATPases, i.e., Bacillus subtilis CopA (43%), Enterococcus hirae CopA (41%), Staphylococcus aureus CopA (41%), E. coli CopA (35%), and E. hirae CopB (31%) (20,40,44,45). Cu ATPase is a member of the CPx-type ATPase superfamily, whose members are typically involved in the transport of heavy metals.…”

Section: Resultsmentioning

confidence: 99%

“…The direction of Cu transport mediated by the P-type ATPase in bacteria is unclear. The inactivation of copA in several bacteria reduces their ability to cope with high levels of Cu, suggesting functions in Cu export (38,44). E. hirae contains two P-type Cu ATPase proteins encoded by copA and copB, which are involved in Cu uptake and efflux, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, this hypothesis needs more experimental data to support it. However, it was previously reported that the inactivation of copA causes changes in oxidative stress resistance in Staphylococcus aureus, where a mutant lacking CopA is sensitive to H 2 O 2 (44). The reduced ability to cope with oxidative stress in A. tumefaciens is associated with an attenuated virulence phenotype (42,51).…”

Section: Vol 191 2009 Analyses Of the Cop Operon In A Tumefaciens mentioning

confidence: 99%

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Functional and Expression Analyses of the cop Operon, Required for Copper Resistance in Agrobacterium tumefaciens

et al. 2009

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The copper resistance determinant copARZ, which encodes a CPx-type copper ATPase efflux protein, a transcriptional regulator, and a putative intracellular copper chaperone, was functionally characterized for the phytopathogenic bacterium Agrobacterium tumefaciens. These genes are transcribed as an operon, and their expression is induced in response to increasing copper and silver ion concentrations in a copR-dependent fashion. Analysis of the copARZ promoter revealed a putative CopR binding box located within the spacer of the ؊35 and ؊10 promoter motifs. In vitro, purified CopR could specifically bind to the box. The inactivation of the copARZ operon or copZ reduces the level of resistance to copper but not to other metal ions. Also, the copARZ operon mutant shows increased sensitivity to the superoxide generators menadione and plumbagin. In addition, the loss of functional copZ does not affect the ability of copper ions to induce the copARZ promoter, indicating that CopZ is not involved in the copper-sensing mechanism of CopR. Altogether, the results demonstrate a crucial role for the copARZ operon as a component of the copper resistance machinery in A. tumefaciens.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Vol 191 2009 Analyses Of the Cop Operon In A Tumefaciens mentioning

confidence: 99%

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Functional and Expression Analyses of the cop Operon, Required for Copper Resistance in Agrobacterium tumefaciens

et al. 2009

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“…On the other hand, the gene encoding the likely copper chaperone CopZ just downstream from copA (Fig. 1A) is induced by copper (24,25), but may not be co-transcribed with copA (24). Although it is not yet known whether the transcription of copZ is also regulated by CsoR, inspection of the intergenic region between copA and copZ does not reveal an obvious candidate CsoR binding site like that found in the copA operator-promoter region, nor have we determined if copZ transcription is altered in the ⌬csoR strain.…”

Section: Discussionmentioning

confidence: 99%

Control of Copper Resistance and Inorganic Sulfur Metabolism by Paralogous Regulators in Staphylococcus aureus

Grossoehme

Kehl-Fie

et al. 2011

Journal of Biological Chemistry

214

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All strains of Staphylococcus aureus encode a putative copper-sensitive operon repressor (CsoR) and one other CsoR-like protein of unknown function. We show here that NWMN_1991 encodes a bona fide Cu(I)-inducible CsoR of a genetically unlinked copA-copZ copper resistance operon in S. aureus strain Newman. In contrast, an unannotated open reading frame found between NWMN_0027 and NWMN_0026 (denoted NWMN_0026.5) encodes a CsoR-like regulator that represses expression of adjacent genes by binding specifically to a pair of canonical operator sites positioned in the NWMN_0027-0026.5 intergenic region. Inspection of these regulated genes suggests a role in assimilation of inorganic sulfur from thiosulfate and vectorial sulfur transfer, and we designate NWMN_ 0026.5 as CstR (CsoR-like sulfur transferase repressor). Expression analysis demonstrates that CsoR and CstR control their respective regulons in response to distinct stimuli with no overlap in vivo. Unlike CsoR, CstR does not form a stable complex with Cu(I); operator binding is instead inhibited by oxidation of the intersubunit cysteine pair to a mixture of disulfide and trisulfide linkages by a likely metabolite of thiosulfate assimilation, sulfite. CsoR is unreactive toward sulfite under the same conditions. We conclude that CsoR and CstR are paralogs in S. aureus that function in the same cytoplasm to control distinct physiological processes.The Gram-positive opportunistic human pathogen Staphylococcus aureus is the causative agent of a wide range of hospital and community-acquired infections that are associated with significant morbidity (1). With the incidence of methicillinresistant strains increasing in previously low prevalence areas (2), new antibiotic therapies that target novel metabolic pathways are urgently needed. One approach is to target those processes that allow a pathogen to respond to environmental stresses that might change depending on the microenvironmental host niche in which the organism finds itself. Resistance to host-mediated copper killing of Escherichia coli (3), Salmonella enterica (4), and Mycobacterium tuberculosis (5, 6) and sulfur assimilation and cysteine biosynthesis in M. tuberculosis (7,8) are two such processes. S. aureus is particularly sensitive to rapid killing when exposed to copper or copper alloy surfaces, justifying this therapeutic direction (9, 10).M. tuberculosis CsoR 6 (copper-sensitive operon repressor) is a founding member of large family of regulators now known collectively to respond to Cu(I), Ni(II), and perhaps other stressors, the structural basis of which is not fully understood (11, 12). All CsoR family proteins lack a known canonical DNA binding domain and are projected to adopt the flat disc-shaped dimer of dimers homotetrameric structure characteristic of Cu(I)-sensing CsoRs, with individual dimers consisting of an antiparallel four-helix bundle flanked by a C-terminal ␣3 helix (13,14). Two cysteine residues on opposite subunits within a dimer make coordination bonds to the Cu(I) ion, with the third ...

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“…All sequenced S. aureus strains have an operon encoding a P1-type ATPase (copA) and a copper binding chaperone homologue (copZ) (37). The expression of the copAZ operon is induced by copper, and mutational analysis has shown that CopA transports copper from the cell and hence is required for S. aureus tolerance of excess copper (37).…”

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confidence: 99%

Copper Stress Induces a Global Stress Response in Staphylococcus aureus and Represses sae and agr Expression and Biofilm Formation

Baker

Sitthisak

Sengupta

et al. 2010

Appl Environ Microbiol

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136

104

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Copper is an important cofactor for many enzymes; however, high levels of copper are toxic. Therefore, bacteria must ensure there is sufficient copper for use as a cofactor but, more importantly, must limit free intracellular levels to prevent toxicity. In this study, we have used DNA microarray to identify Staphylococcus aureus copper-responsive genes. Transcriptional profiling of S. aureus SH1000 grown in excess copper identified a number of genes which fall into four groups, suggesting that S. aureus has four main mechanisms for adapting to high levels of environmental copper, as follows: (i) induction of direct copper homeostasis mechanisms; (ii) increased oxidative stress resistance; (iii) expression of the misfolded protein response; and (iv) repression of a number of transporters and global regulators such as Agr and Sae. Our experimental data confirm that resistance to oxidative stress and particularly to H 2 O 2 scavenging is an important S. aureus copper resistance mechanism. Our previous studies have demonstrated that Eap and Emp proteins, which are positively regulated by Agr and Sae, are required for biofilm formation under low-iron growth conditions. Our transcriptional analysis has confirmed that sae, agr, and eap are repressed under high-copper conditions and that biofilm formation is indeed repressed under high-copper conditions. Therefore, our results may provide an explanation for how copper films can prevent biofilm formation on catheters.

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Molecular characterization of the copper transport system in Staphylococcus aureus

Cited by 64 publications

References 41 publications

Functional and Expression Analyses of the cop Operon, Required for Copper Resistance in Agrobacterium tumefaciens

Functional and Expression Analyses of the cop Operon, Required for Copper Resistance in Agrobacterium tumefaciens

Control of Copper Resistance and Inorganic Sulfur Metabolism by Paralogous Regulators in Staphylococcus aureus

Copper Stress Induces a Global Stress Response in Staphylococcus aureus and Represses sae and agr Expression and Biofilm Formation

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