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As iron (Fe) SOD is absent in the human host, this enzyme is a promising molecular target for drug development against trypanosomatids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We obtained\n                      <jats:italic>Leishmania infantum<\/jats:italic>\n                      mutant clones with lower FeSOD-A expression and investigated their phenotypes. Our attempts to delete this enzyme-coding gene using three different methodologies (conventional allelic replacement or two different CRISPR\/methods) failed, as\n                      <jats:italic>FeSOD-A<\/jats:italic>\n                      gene copies were probably retained by aneuploidy or gene amplification. Promastigote forms of WT and mutant parasites were used in quantitative reverse-transcription polymerase chain reaction (RT-qPCR) and western blot analyses, and these parasite forms were also used to assess drug susceptibility. RT-qPCR and western blot analyses revealed that FeSOD-A transcript and protein levels were lower in\n                      <jats:italic>FeSOD-A<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212\/<\/jats:italic>\n                        +\n                      <\/jats:sup>\n                      <jats:italic>L. infantum<\/jats:italic>\n                      mutant clones than in the wild-type (WT) parasite. The decrease in FeSOD-A expression in\n                      <jats:italic>L. infantum<\/jats:italic>\n                      did not interfere with the parasite growth or susceptibility to amphotericin B. Surprisingly,\n                      <jats:italic>FeSOD-A<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212\/<\/jats:italic>\n                        +\n                      <\/jats:sup>\n                      <jats:italic>L. infantum<\/jats:italic>\n                      mutant clones were 1.5- to 2.0-fold more resistant to trivalent antimony and 2.4- to 2.7-fold more resistant to miltefosine. To investigate whether the decrease in FeSOD-A expression was compensated by other enzymes, the transcript levels of five FeSODs and six enzymes from the antioxidant defence system were assessed by RT-qPCR. The transcript level of the enzyme ascorbate peroxidase increased in both the\n                      <jats:italic>FeSOD-A<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212\/<\/jats:italic>\n                        +\n                      <\/jats:sup>\n                      mutants tested. The\n                      <jats:italic>FeSOD-A<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212\/<\/jats:italic>\n                        +\n                      <\/jats:sup>\n                      mutant parasites were 1.4- to 1.75-fold less tolerant to oxidative stress generated by menadione. Infection analysis using THP-1 macrophages showed that 72\u00a0h post-infection, the number of infected macrophages and their intracellular multiplication rate were lower in the\n                      <jats:italic>FeSOD-A<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212\/<\/jats:italic>\n                        +\n                      <\/jats:sup>\n                      mutant clones than in the WT parasite.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The unsuccessful attempts to delete\n                      <jats:italic>FeSOD-A<\/jats:italic>\n                      suggest that this gene is essential in\n                      <jats:italic>L. infantum<\/jats:italic>\n                      . This enzyme plays an important role in the defence against oxidative stress and infectivity in THP-1 macrophages. FeSOD-A-deficient\n                      <jats:italic>L. infantum<\/jats:italic>\n                      parasites deregulate their metabolic pathways related to antimony and miltefosine resistance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphic Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s13071-021-04838-8","type":"journal-article","created":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T07:02:58Z","timestamp":1626332578000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Downregulation of FeSOD-A expression in Leishmania infantum alters trivalent antimony and miltefosine susceptibility"],"prefix":"10.1186","volume":"14","author":[{"given":"Ana Maria Murta","family":"Santi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula Alves","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella Fernandes Martins","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8523-2155","authenticated-orcid":false,"given":"Silvane Maria Fonseca","family":"Murta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,15]]},"reference":[{"key":"4838_CR1","unstructured":"WHO. 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