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Here, we aimed to elucidate the molecular mechanisms underlying the low susceptibility of the Gram-negative model organism\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      to auranofin when compared to the Gram-positive model organism\n                      <jats:italic>Bacillus subtilis<\/jats:italic>\n                      . The proteome response of\n                      <jats:italic>E. coli<\/jats:italic>\n                      exposed to auranofin suggests a combination of inactivation of thiol-containing enzymes and the induction of systemic oxidative stress. Susceptibility tests in\n                      <jats:italic>E. coli<\/jats:italic>\n                      mutants lacking proteins upregulated upon auranofin treatment suggested that none of them are directly involved in\n                      <jats:italic>E. coli<\/jats:italic>\n                      \u2019s high tolerance to auranofin.\n                      <jats:italic>E. coli<\/jats:italic>\n                      cells lacking the efflux pump component TolC were more sensitive to auranofin treatment, but not to an extent that would fully explain the observed difference in susceptibility of Gram-positive and Gram-negative organisms. We thus tested whether\n                      <jats:italic>E. coli<\/jats:italic>\n                      \u2019s thioredoxin reductase (TrxB) is inherently less sensitive to auranofin than TrxB from\n                      <jats:italic>B. subtilis<\/jats:italic>\n                      , which was not the case. However,\n                      <jats:italic>E. coli<\/jats:italic>\n                      strains lacking the low-molecular-weight thiol glutathione, but not glutathione reductase, showed a high susceptibility to auranofin. Bacterial cells expressing the genetically encoded redox probe roGFP2 allowed us to observe the oxidation of cellular protein thiols\n                      <jats:italic>in situ<\/jats:italic>\n                      . Based on our findings, we hypothesize that auranofin leads to a global disturbance in the cellular thiol redox homeostasis in bacteria, but Gram-negative bacteria are inherently more resistant due to the presence of drug export systems and high cellular concentrations of glutathione.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Auranofin is an FDA-approved drug for the treatment of rheumatoid arthritis. However, it has also high antibacterial activity, in particular against Gram-positive organisms. In the current antibiotics crisis, this would make it an ideal candidate for drug repurposing. However, its much lower activity against Gram-negative organisms prevents its broad-spectrum application. Here we show that, on the level of the presumed target, there is no difference in susceptibility between Gram-negative and Gram-positive species: thioredoxin reductases from both\n                        <jats:italic>Escherichia coli<\/jats:italic>\n                        and\n                        <jats:italic>Bacillus subtilis<\/jats:italic>\n                        are equally inhibited by auranofin. In both species, auranofin treatment leads to oxidative protein modification on a systemic level, as monitored by proteomics and the genetically encoded redox probe roGFP2. The single largest contributor to\n                        <jats:italic>E. coli<\/jats:italic>\n                        \u2019s relative resistance to auranofin seems to be the low-molecular-weight thiol glutathione, which is absent in\n                        <jats:italic>B. subtilis<\/jats:italic>\n                        and other Gram-positive species.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00138-24","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T11:44:02Z","timestamp":1728387842000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Comparison of the mechanism of antimicrobial action of the gold(I) compound auranofin in Gram-positive and Gram-negative bacteria"],"prefix":"10.1128","volume":"12","author":[{"given":"La\u00edsa","family":"Quadros Bars\u00e9","sequence":"first","affiliation":[{"name":"Medical Faculty, Institute of Biochemistry and Pathobiochemistry\u2013Microbial Biochemistry, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Ulfig","sequence":"additional","affiliation":[{"name":"Medical Faculty, Institute of Biochemistry and Pathobiochemistry\u2013Microbial Biochemistry, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marharyta","family":"Varatnitskaya","sequence":"additional","affiliation":[{"name":"Medical Faculty, Institute of Biochemistry and Pathobiochemistry\u2013Microbial Biochemistry, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"V\u00e1zquez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Faculty of Biology and Biotechnology, Applied Microbiology, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihyun","family":"Yoo","sequence":"additional","affiliation":[{"name":"Medical Faculty, Institute of Biochemistry and Pathobiochemistry\u2013Microbial Biochemistry, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid M.","family":"Imann","sequence":"additional","affiliation":[{"name":"Medical Faculty, Institute of Biochemistry and Pathobiochemistry\u2013Microbial Biochemistry, Ruhr University Bochum, Bochum, Germany"},{"name":"Institute of Electrical Engineering and Applied Sciences\u2013Molecular Biology, Westphalian University of Applied Sciences, Recklinghausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Lupilov","sequence":"additional","affiliation":[{"name":"Medical Faculty, Institute of Biochemistry and Pathobiochemistry\u2013Microbial Biochemistry, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Fischer","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center, Justus Liebig University Giessen, Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Becker","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center, Justus Liebig University Giessen, Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia E.","family":"Bandow","sequence":"additional","affiliation":[{"name":"Faculty of Biology and Biotechnology, Applied Microbiology, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5666-9681","authenticated-orcid":true,"given":"Lars I.","family":"Leichert","sequence":"additional","affiliation":[{"name":"Medical Faculty, Institute of Biochemistry and Pathobiochemistry\u2013Microbial Biochemistry, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.16.020916"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2019.10.008"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S173867"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-019-0357-1"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13798"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijge.2011.09.015"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/ed083p728"},{"key":"e_1_3_3_9_2","first-page":"279","article-title":"Gold complexes in the treatment of rheumatoid arthritis","volume":"41","author":"Messori L","year":"2004","unstructured":"Messori L, Marcon G. 2004. 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