Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus.
To gain a better insight of how Copper (Cu) ions toxify cells, metabolomic analyses were performed in S. aureus strains that lacks the described Cu ion detoxification systems (ΔcopBL ΔcopAZ; cop-). Exposure of the cop- strain to Cu(II) resulted in an increase in the concentrations of metabolites uti...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-05-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1011393 |
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| author | Javiera Norambuena Hassan Al-Tameemi Hannah Bovermann Jisun Kim William N Beavers Eric P Skaar Dane Parker Jeffrey M Boyd |
| author_facet | Javiera Norambuena Hassan Al-Tameemi Hannah Bovermann Jisun Kim William N Beavers Eric P Skaar Dane Parker Jeffrey M Boyd |
| author_sort | Javiera Norambuena |
| collection | DOAJ |
| description | To gain a better insight of how Copper (Cu) ions toxify cells, metabolomic analyses were performed in S. aureus strains that lacks the described Cu ion detoxification systems (ΔcopBL ΔcopAZ; cop-). Exposure of the cop- strain to Cu(II) resulted in an increase in the concentrations of metabolites utilized to synthesize phosphoribosyl diphosphate (PRPP). PRPP is created using the enzyme phosphoribosylpyrophosphate synthetase (Prs) which catalyzes the interconversion of ATP and ribose 5-phosphate to PRPP and AMP. Supplementing growth medium with metabolites requiring PRPP for synthesis improved growth in the presence of Cu(II). A suppressor screen revealed that a strain with a lesion in the gene coding adenine phosphoribosyltransferase (apt) was more resistant to Cu. Apt catalyzes the conversion of adenine with PRPP to AMP. The apt mutant had an increased pool of adenine suggesting that the PRPP pool was being redirected. Over-production of apt, or alternate enzymes that utilize PRPP, increased sensitivity to Cu(II). Increasing or decreasing expression of prs resulted in decreased and increased sensitivity to growth in the presence of Cu(II), respectively. We demonstrate that Prs is inhibited by Cu ions in vivo and in vitro and that treatment of cells with Cu(II) results in decreased PRPP levels. Lastly, we establish that S. aureus that lacks the ability to remove Cu ions from the cytosol is defective in colonizing the airway in a murine model of acute pneumonia, as well as the skin. The data presented are consistent with a model wherein Cu ions inhibits pentose phosphate pathway function and are used by the immune system to prevent S. aureus infections. |
| format | Article |
| id | doaj-art-3f1de80caeeb4e4e89cb47459d3ed5dc |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2023-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-3f1de80caeeb4e4e89cb47459d3ed5dc2025-08-20T01:48:29ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-05-01195e101139310.1371/journal.ppat.1011393Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus.Javiera NorambuenaHassan Al-TameemiHannah BovermannJisun KimWilliam N BeaversEric P SkaarDane ParkerJeffrey M BoydTo gain a better insight of how Copper (Cu) ions toxify cells, metabolomic analyses were performed in S. aureus strains that lacks the described Cu ion detoxification systems (ΔcopBL ΔcopAZ; cop-). Exposure of the cop- strain to Cu(II) resulted in an increase in the concentrations of metabolites utilized to synthesize phosphoribosyl diphosphate (PRPP). PRPP is created using the enzyme phosphoribosylpyrophosphate synthetase (Prs) which catalyzes the interconversion of ATP and ribose 5-phosphate to PRPP and AMP. Supplementing growth medium with metabolites requiring PRPP for synthesis improved growth in the presence of Cu(II). A suppressor screen revealed that a strain with a lesion in the gene coding adenine phosphoribosyltransferase (apt) was more resistant to Cu. Apt catalyzes the conversion of adenine with PRPP to AMP. The apt mutant had an increased pool of adenine suggesting that the PRPP pool was being redirected. Over-production of apt, or alternate enzymes that utilize PRPP, increased sensitivity to Cu(II). Increasing or decreasing expression of prs resulted in decreased and increased sensitivity to growth in the presence of Cu(II), respectively. We demonstrate that Prs is inhibited by Cu ions in vivo and in vitro and that treatment of cells with Cu(II) results in decreased PRPP levels. Lastly, we establish that S. aureus that lacks the ability to remove Cu ions from the cytosol is defective in colonizing the airway in a murine model of acute pneumonia, as well as the skin. The data presented are consistent with a model wherein Cu ions inhibits pentose phosphate pathway function and are used by the immune system to prevent S. aureus infections.https://doi.org/10.1371/journal.ppat.1011393 |
| spellingShingle | Javiera Norambuena Hassan Al-Tameemi Hannah Bovermann Jisun Kim William N Beavers Eric P Skaar Dane Parker Jeffrey M Boyd Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus. PLoS Pathogens |
| title | Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus. |
| title_full | Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus. |
| title_fullStr | Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus. |
| title_full_unstemmed | Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus. |
| title_short | Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus. |
| title_sort | copper ions inhibit pentose phosphate pathway function in staphylococcus aureus |
| url | https://doi.org/10.1371/journal.ppat.1011393 |
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