{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T16:46:05Z","timestamp":1789922765605,"version":"4.0.1"},"reference-count":53,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2011,3,1]],"date-time":"2011-03-01T00:00:00Z","timestamp":1298937600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2011,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Anthrax lethal toxin (LT) is the major virulence factor for<jats:italic>Bacillus anthracis<\/jats:italic>. The lethal factor (LF) component of this bipartite toxin is a protease which, when transported into the cellular cytoplasm, cleaves mitogen-activated protein kinase kinase (MEK) family proteins and induces rapid toxicity in mouse macrophages through activation of the Nlrp1b inflammasome. A high-throughput screen was performed to identify synergistic LT-inhibitory drug combinations from within a library of approved drugs and molecular probes. From this screen we discovered that auranofin, an organogold compound with anti-inflammatory activity, strongly inhibited LT-mediated toxicity in mouse macrophages. Auranofin did not inhibit toxin transport into cells or MEK cleavage but inhibited both LT-mediated caspase-1 activation and caspase-1 catalytic activity. Thus, auranofin inhibited LT-mediated toxicity by preventing activation of the Nlrp1b inflammasome and the downstream actions that occur in response to the toxin. Idebenone, an analog of coenzyme Q, synergized with auranofin to increase its protective effect. We found that idebenone functions as an inhibitor of voltage-gated potassium channels and thus likely mediates synergy through inhibition of the potassium fluxes which have been shown to be required for Nlrp1b inflammasome activation.<\/jats:p>","DOI":"10.1128\/aac.00772-10","type":"journal-article","created":{"date-parts":[[2010,12,14]],"date-time":"2010-12-14T04:44:21Z","timestamp":1292301861000},"page":"1028-1035","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":28,"title":["Auranofin Protects against Anthrax Lethal Toxin-Induced Activation of the Nlrp1b Inflammasome"],"prefix":"10.1128","volume":"55","author":[{"given":"Zachary L.","family":"Newman","sequence":"first","affiliation":[{"name":"National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Sirianni","sequence":"additional","affiliation":[{"name":"Zalicus Inc., Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Mawhinney","sequence":"additional","affiliation":[{"name":"Zalicus Inc., Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Zalicus Inc., Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen H.","family":"Leppla","sequence":"additional","affiliation":[{"name":"National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahtab","family":"Moayeri","sequence":"additional","affiliation":[{"name":"National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Johansen","sequence":"additional","affiliation":[{"name":"Zalicus Inc., Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007913"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-3623(96)00419-3"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.54.4.329"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1337088100"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1724"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.19.2061"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2004.07.073"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(84)90007-4"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(99)00127-2"},{"key":"e_1_3_2_11_2","first-page":"335","volume":"79","year":"1990","unstructured":"Danis, V. A., A. J. Kulesz, D. S. Nelson, and P. M. Brooks. 1990. The effect of gold sodium thiomalate and auranofin on lipopolysaccharide-induced interleukin-1 production by blood monocytes in vitro: variation in healthy subjects and patients with arthritis. Clin. Exp. Immunol. 79:335-340.","journal-title":"Clin. Exp. Immunol."},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2008.03997.x"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707370105"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.8.5245"},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0031-6997(25)06847-4","volume":"47","year":"1995","unstructured":"Greco, W. R., G. Bravo, and J. C. Parsons. 1995. The search for synergy: a critical review from a response surface perspective. Pharmacol. Rev. 47:331-385.","journal-title":"Pharmacol. Rev."},{"key":"e_1_3_2_16_2","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/S0026-895X(25)10594-4","volume":"45","year":"1994","unstructured":"Grissmer, S., et al. 1994. Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol. Pharmacol. 45:1227-1234.","journal-title":"Mol. Pharmacol."},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003130"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115788"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4943(89)90014-9"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2003.9"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.11.5981"},{"key":"e_1_3_2_22_2","first-page":"357","volume":"36","year":"1984","unstructured":"Kakihana, M., N. Yamazaki, and A. Nagaoka. 1984. Effects of idebenone (CV-2619) on the concentrations of acetylcholine and choline in various brain regions of rats with cerebral ischemia. Jpn. J. Pharmacol. 36:357-363.","journal-title":"Jpn. J. Pharmacol."},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4943(89)90007-1"},{"key":"e_1_3_2_24_2","first-page":"415","volume":"47","year":"2008","unstructured":"Kastbom, A., et al. 2008. Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project). Rheumatology (Oxford) 47:415-417.","journal-title":"Rheumatology (Oxford)"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/36.5.560"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.52.2.314"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1549"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2008.01220.x"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00276-09"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4943(92)90058-C"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400908"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.63.3.547"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132715"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-009-1005-0"},{"key":"e_1_3_2_35_2","first-page":"439","volume":"6","year":"2009","unstructured":"Moayeri, M., and S. H. Leppla. 2009. Cellular and systemic effects of anthrax lethal toxin and edema toxin. Mol. Aspects Med. 6:439-455.","journal-title":"Mol. Aspects Med."},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.6.6.3991"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.07.039"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00730-09"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000906"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-12-04798.2003"},{"key":"e_1_3_2_41_2","first-page":"1296","volume":"65","year":"2008","unstructured":"Pandolfo, M. 2008. Friedreich ataxia. Arch. Neurol. 65:1296-1303.","journal-title":"Arch. Neurol."},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1006\/prep.2000.1208"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4402195"},{"key":"e_1_3_2_44_2","unstructured":"Numerical recipes in C: the art of scientific computing 1997"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.3109\/03009748809098794"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.192773"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1023\/B:JOCI.0000010424.41475.17"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar2397"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/0049-0172(87)90017-5"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705687200"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4943(89)90011-3"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.11.120"},{"key":"e_1_3_2_53_2","first-page":"332","volume":"10","year":"2008","unstructured":"Wickliffe, K. E., S. H. Leppla, and M. Moayeri. 2008. Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell. Microbiol. 10:332-343.","journal-title":"Cell. Microbiol."},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2006.11.008"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00772-10","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00772-10","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T18:53:40Z","timestamp":1740768820000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00772-10"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,3]]},"references-count":53,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2011,3]]}},"alternative-id":["10.1128\/AAC.00772-10"],"URL":"https:\/\/doi.org\/10.1128\/aac.00772-10","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,3]]},"assertion":[{"value":"2010-06-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2010-11-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-02-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}