Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus
Open Access
- 26 May 2023
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 19 (5), e1011393
- https://doi.org/10.1371/journal.ppat.1011393
Abstract
To gain a better insight of how 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. Antimicrobial resistance is a global health emergency. There is an increasing demand to develop new drugs and repurpose chemotherapeutics to prevent and treat infections. Metals and metal ions have been used as effective antimicrobials for millennia. This effectiveness is likely due to their ability to simultaneously inhibit multiple cellular processes. Copper (Cu) is a metal that has been used by humans as a prophylactic. Furthermore, the human immune system utilizes Cu to aid bacterial killing or growth inhibition. The human pathogen Staphylococcus aureus has two described Cu ion detoxification systems, underscoring the efficacy of Cu ions to negatively impact S. aureus growth and survival. Questions remain about how bacteria are toxified by Cu ions. Understanding how Cu kills and inhibits bacterial growth will provide useful information for designing and implementing antimicrobial chemotherapy to decrease bacteria burden. Herein, we demonstrate that the essential enzyme Prs is a target of Cu ions in S. aureus. Using mouse models of pneumonia and skin infections, we demonstrate that S. aureus that cannot effectively remove Cu ions from the inside of the cell are defective in colonizing tissues.Keywords
Funding Information
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (1R01AI139100-01)
- Directorate for Biological Sciences (1750624)
- National Institute of Food and Agriculture (NE−1028)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI150701)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI138581)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI145992)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R21AI153646)
- New Jersey Health Foundation (PC 142-22)
- New Jersey Commission on Cancer Research (COCR22RBG005)
This publication has 80 references indexed in Scilit:
- Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene ExpressionCell, 2013
- Copper Homeostasis at the Host-Pathogen InterfaceOnline Journal of Public Health Informatics, 2012
- Control of Copper Resistance and Inorganic Sulfur Metabolism by Paralogous Regulators in Staphylococcus aureusOnline Journal of Public Health Informatics, 2011
- Metabolomic Analysis and Visualization Engine for LC−MS DataAnalytical Chemistry, 2010
- Killing of Bacteria by Copper Surfaces Involves Dissolved CopperApplied and Environmental Microbiology, 2010
- Phosphoribosylpyrophosphate synthetase (PrsA) variants alter cellular pools of ribose 5-phosphate and influence thiamine synthesis in Salmonella entericaMicrobiology, 2010
- A Role for the ATP7A Copper-transporting ATPase in Macrophage Bactericidal ActivityOnline Journal of Public Health Informatics, 2009
- The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicityProceedings of the National Academy of Sciences of the United States of America, 2009
- Improved single-copy integration vectors for Staphylococcus aureusJournal of Microbiological Methods, 2007
- The toxic shock syndrome exotoxin structural gene is not detectably transmitted by a prophageNature, 1983