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These conditions can include access to nutrients, such as amino acids, and exposure to toxic compounds, like copper. To investigate the ability of\n                      <jats:italic toggle=\"yes\">Brucella abortus<\/jats:italic>\n                      , a facultative intracellular pathogen responsible for a major zoonosis, to cope with copper, we performed a Tn-seq analysis to identify copper-sensitive mutants. Unexpectedly, we realized that classical copper resistance systems (involving CopA and CueO homologs) do not appear to be robustly needed, while histidine and purine biosynthesis pathways are crucial to cope with copper. We show that\n                      <jats:italic toggle=\"yes\">hisA<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">hisB<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">hisC,<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">hisD<\/jats:italic>\n                      mutants are auxotrophic for histidine and sensitive to copper. This suggests that the reported attenuation of\n                      <jats:italic toggle=\"yes\">his<\/jats:italic>\n                      mutants in macrophages could be based on auxotrophy and\/or copper sensitivity. Therefore, we generated suppressor strains with a restored resistance to copper for\n                      <jats:italic toggle=\"yes\">hisC<\/jats:italic>\n                      , but still auxotrophs for histidine. Our data suggest that this suppression is due to the overproduction of a homolog of OppA, a periplasmic oligopeptide-binding protein. Analysis of these suppressors shows that the absence of histidine biosynthesis capacity, and not copper sensitivity, is required for optimal growth of\n                      <jats:italic toggle=\"yes\">B. abortus<\/jats:italic>\n                      in macrophages.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Investigating conditions in which intracellular bacteria grow inside host cells is challenging and often involves the characterization of attenuated bacterial mutants obtained by screening. But a single mutant can display two different phenotypes related to intracellular conditions. It was the case for histidine auxotrophs of\n                        <jats:italic toggle=\"yes\">Brucella abortus<\/jats:italic>\n                        , an important zoonotic pathogen. These histidine auxotrophs are attenuated in a macrophage cell line, and they are also sensitive to copper stress. Using a suppressor strain still auxotroph for histidine but with an improved resistance to copper, we show that histidine auxotrophy, and not sensitivity to copper excess, is the main cause of attenuation in the conditions tested here.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00492-25","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T14:00:16Z","timestamp":1770213616000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["<i>Brucella abortus<\/i>\n                    histidine auxotrophs are copper 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