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More recently, it has shown some efficacy as therapy against protozoan pathogens and certain cancers, suggesting a wide range of biological activities. We used an<jats:italic>ex vivo<\/jats:italic>system to screen several thiuram disulfide compounds for antileishmanial activity. We found five compounds (compound identifier [CID] 7188, 5455, 95876, 12892, and 3117 [disulfiram]) with anti-<jats:italic>Leishmania<\/jats:italic>activity at nanomolar concentrations. We further evaluated these compounds with the addition of divalent metal salts based on studies that indicated these salts could potentiate the action of disulfiram. In addition, clinical studies suggested that zinc has some efficacy in treating cutaneous leishmaniasis. Several divalent metal salts were evaluated at 1 \u03bcM, which is lower than the normal levels of copper and zinc in plasma of healthy individuals. The leishmanicidal activity of disulfiram and CID 7188 were enhanced by several divalent metal salts at 1 \u03bcM. The<jats:italic>in vitro<\/jats:italic>therapeutic index (IVTI) of disulfiram and CID 7188 increased 12- and 2.3-fold, respectively, against<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">L. major<\/jats:named-content>when combined with ZnCl<jats:sub>2<\/jats:sub>. The combination of disulfiram with ZnSO<jats:sub>4<\/jats:sub>resulted in a 1.8-fold increase in IVTI against<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">L. donovani<\/jats:named-content>. This novel combination of thiuram disulfides and divalent metal ions salts could have application as topical and\/or oral therapies for treatment of cutaneous and visceral leishmaniasis.<\/jats:p>","DOI":"10.1128\/aac.05131-14","type":"journal-article","created":{"date-parts":[[2015,8,4]],"date-time":"2015-08-04T02:44:26Z","timestamp":1438656266000},"page":"6463-6470","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Antileishmanial Activity of Disulfiram and Thiuram Disulfide Analogs in an<i>Ex Vivo<\/i>Model System Is Selectively Enhanced by the Addition of Divalent Metal Ions"],"prefix":"10.1128","volume":"59","author":[{"given":"Alex G.","family":"Peniche","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Escuela de Ciencias B\u00e1sicas, Facultad de Salud, Universidad del Valle, Cali, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Renslo","sequence":"additional","affiliation":[{"name":"Small Molecule Discovery Center, Center for Discovery and Innovation in Parasitic Diseases, and Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Melby","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno L.","family":"Travi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003053"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/425747"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2007.00554.x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-013-0133-0"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1086\/377133"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmaid.2006.09.004"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.10.92"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD005067.pub3"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1202657"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087366"},{"key":"e_1_3_2_12_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/0006-2952(90)90680-J","article-title":"Antimalarial activity of diethyldithiocarbamate. 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