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The very limited arsenal of anti-\n                      <jats:italic toggle=\"yes\">T<\/jats:italic>\n                      .\n                      <jats:italic toggle=\"yes\">cruzi<\/jats:italic>\n                      treatments calls for the development of new drugs. Recently, a library of 3-benzylmenadione derivatives was synthesized, with cruzidione being the most efficient and specific compound against the parasite. To decipher its mode of action, we used the yeast\n                      <jats:italic toggle=\"yes\">Saccharomyces cerevisiae<\/jats:italic>\n                      as a model. Evidence pinpointed at the heme A synthase Cox15 as a primary target of cruzidione: (i) a mutation in Cox15 (i.e., S429F) renders the yeast cells highly sensitive to the drug, (ii) treatment with cruzidione led to the loss of cytochrome\n                      <jats:italic toggle=\"yes\">c<\/jats:italic>\n                      oxidase, an enzyme that relies on heme A as an essential cofactor, and (iii) replacement of the yeast Cox15 by\n                      <jats:italic toggle=\"yes\">T. cruzi<\/jats:italic>\n                      enzyme resulted in a high sensitivity to cruzidione. We then investigated the effect of cruzidione in\n                      <jats:italic toggle=\"yes\">T. cruzi<\/jats:italic>\n                      and observed a significant reduction in the heme contents, most likely involving the inhibition of the heme A synthase. This, in turn, led to a decrease in O\n                      <jats:sub>2<\/jats:sub>\n                      consumption by the parasite. Finally, using the yeast model, we showed that, similar to what we previously found for the antimalarial benzylmenadione plasmodione, NADH-dehydrogenase plays a key role in cruzidione bioactivation. We proposed that the reduced benzoylmenadione metabolites, produced by the reaction with NADH-dehydrogenase, act as Cox15 inhibitors. This study, through the identification of the mode of action of cruzidione, highlighted Cox15 as a novel target for antiparasitic drugs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01161-25","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T15:05:06Z","timestamp":1765379106000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["The heme A synthase Cox15, as a target of redox-active 3-benzylmenadiones with antiparasitic activity"],"prefix":"10.1128","volume":"70","author":[{"given":"Marcelo L.","family":"Merli","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02tphfq59","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) - Universidad Nacional de Rosario (UNR)","place":["Rosario, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Serot","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjwb503","id-type":"ROR","asserted-by":"publisher"}],"name":"Universit\u00e9 Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)","place":["Gif-sur-Yvette, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Valli\u00e8res","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjwb503","id-type":"ROR","asserted-by":"publisher"}],"name":"Universit\u00e9 Paris-Saclay, CNRS UPR 2301, Institut de Chimie des Substances Naturelles (ICSN)","place":["Gif-sur-Yvette, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia A.","family":"Cricco","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02tphfq59","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) - 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