Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureus
Abstract Disulfiram (Antabuse®) is a prescription alcohol sobriety aid that has shown repurposing potential as an antibacterial drug for infections due to Gram-positive bacteria. In this investigation, we sought to define the principal mechanisms that disulfiram operates as a growth inhibitor of Sta...
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Nature Portfolio
2025-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-00078-3 |
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| author | Timothy E. Long Surya Teja Naidu Emily G. Hissom Yogesh Meka Hasitha Chavva Kathleen C. Brown Meagan E. Valentine Jun Fan James Denvir Donald A. Primerano Hongwei D. Yu Monica A. Valentovic |
| author_facet | Timothy E. Long Surya Teja Naidu Emily G. Hissom Yogesh Meka Hasitha Chavva Kathleen C. Brown Meagan E. Valentine Jun Fan James Denvir Donald A. Primerano Hongwei D. Yu Monica A. Valentovic |
| author_sort | Timothy E. Long |
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| description | Abstract Disulfiram (Antabuse®) is a prescription alcohol sobriety aid that has shown repurposing potential as an antibacterial drug for infections due to Gram-positive bacteria. In this investigation, we sought to define the principal mechanisms that disulfiram operates as a growth inhibitor of Staphylococcus aureus using differential transcriptomic, metabolomic, bioenergetic, and phenotypic growth analyses. The RNA-seq transcriptome analysis revealed that disulfiram induces oxidative stress, redox imbalance, metal acquisition, and the biosynthesis of pantothenate, coenzyme A, thiamine, menaquinone, siderophores/metallophores, and bacillithiol. The metabolomic analysis indicated that disulfiram depletes coenzyme A and attenuates the catabolism of glucose, pyruvate, and NADH. Conversely, disulfiram appeared to up-regulate arginine catabolism for ATP production and accelerate citrate consumption that was attributed to induction of siderophore biosynthesis (i.e., staphyloferrin). The bioenergetic studies further revealed that the primary metabolite of disulfiram (i.e., diethyldithiocarbamate) is likely involved in the mechanism of action as an inhibitor of oxidative phosphorylation and chelating agent of iron and other metals. In the final analysis, disulfiram inhibits the growth of S. aureus by inducing perturbations in central glucose catabolism and redox imbalance (e.g., oxidative stress). Moreover, the chelation of metal ions and antagonism of the respiratory chain by diethyldithiocarbamate are believed to contribute to the inhibition of cell replication. |
| format | Article |
| id | doaj-art-ade8359b7ebe43bfb667a06da8b18100 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-ade8359b7ebe43bfb667a06da8b181002025-08-20T03:42:27ZengNature PortfolioScientific Reports2045-23222025-05-0115111510.1038/s41598-025-00078-3Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureusTimothy E. Long0Surya Teja Naidu1Emily G. Hissom2Yogesh Meka3Hasitha Chavva4Kathleen C. Brown5Meagan E. Valentine6Jun Fan7James Denvir8Donald A. Primerano9Hongwei D. Yu10Monica A. Valentovic11Department of Pharmaceutical Sciences, School of Pharmacy, Marshall UniversityDepartment of Pharmaceutical Sciences, School of Pharmacy, Marshall UniversityDepartment of Pharmaceutical Sciences, School of Pharmacy, Marshall UniversityDepartment of Pharmaceutical Sciences, School of Pharmacy, Marshall UniversityDepartment of Pharmaceutical Sciences, School of Pharmacy, Marshall UniversityDepartment of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall UniversityDepartment of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall UniversityDepartment of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall UniversityDepartment of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall UniversityDepartment of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall UniversityDepartment of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall UniversityDepartment of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall UniversityAbstract Disulfiram (Antabuse®) is a prescription alcohol sobriety aid that has shown repurposing potential as an antibacterial drug for infections due to Gram-positive bacteria. In this investigation, we sought to define the principal mechanisms that disulfiram operates as a growth inhibitor of Staphylococcus aureus using differential transcriptomic, metabolomic, bioenergetic, and phenotypic growth analyses. The RNA-seq transcriptome analysis revealed that disulfiram induces oxidative stress, redox imbalance, metal acquisition, and the biosynthesis of pantothenate, coenzyme A, thiamine, menaquinone, siderophores/metallophores, and bacillithiol. The metabolomic analysis indicated that disulfiram depletes coenzyme A and attenuates the catabolism of glucose, pyruvate, and NADH. Conversely, disulfiram appeared to up-regulate arginine catabolism for ATP production and accelerate citrate consumption that was attributed to induction of siderophore biosynthesis (i.e., staphyloferrin). The bioenergetic studies further revealed that the primary metabolite of disulfiram (i.e., diethyldithiocarbamate) is likely involved in the mechanism of action as an inhibitor of oxidative phosphorylation and chelating agent of iron and other metals. In the final analysis, disulfiram inhibits the growth of S. aureus by inducing perturbations in central glucose catabolism and redox imbalance (e.g., oxidative stress). Moreover, the chelation of metal ions and antagonism of the respiratory chain by diethyldithiocarbamate are believed to contribute to the inhibition of cell replication.https://doi.org/10.1038/s41598-025-00078-3 |
| spellingShingle | Timothy E. Long Surya Teja Naidu Emily G. Hissom Yogesh Meka Hasitha Chavva Kathleen C. Brown Meagan E. Valentine Jun Fan James Denvir Donald A. Primerano Hongwei D. Yu Monica A. Valentovic Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureus Scientific Reports |
| title | Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureus |
| title_full | Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureus |
| title_fullStr | Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureus |
| title_full_unstemmed | Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureus |
| title_short | Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureus |
| title_sort | disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of staphylococcus aureus |
| url | https://doi.org/10.1038/s41598-025-00078-3 |
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