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The global spread of methicillin-resistant\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      (MRSA) necessitates innovative therapeutic approaches beyond traditional antibiotics.\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      virulence mechanisms remain a critical concern. Targeting histidinol dehydrogenase (HisD), a key enzyme in histidine biosynthesis, presents a novel anti-virulence strategy. We used the derivative strains of Newman strains (\u0394\n                      <jats:italic toggle=\"yes\">hisD<\/jats:italic>\n                      , \u0394\n                      <jats:italic toggle=\"yes\">hisD<\/jats:italic>\n                      ::pRAB-\n                      <jats:italic toggle=\"yes\">hisD,<\/jats:italic>\n                      and WT::pRAB-\n                      <jats:italic toggle=\"yes\">hisD<\/jats:italic>\n                      ) and clinical strains to study the role of HisD in the pathogenicity of\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      . HisD inhibition by pixantrone was further evaluated. The absence of\n                      <jats:italic toggle=\"yes\">hisD<\/jats:italic>\n                      significantly reduced hemolytic activity and biofilm formation, accompanied by the downregulation of virulence genes (\n                      <jats:italic toggle=\"yes\">hla<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">coa<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">hlgA-C<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">lukE\/S\/F<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">NWMN_1873<\/jats:italic>\n                      ) and the\n                      <jats:italic toggle=\"yes\">saeR\/S<\/jats:italic>\n                      two-component system (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.05). The expression of biofilm-inhibiting proteases was elevated, notably Aur and ScpA. Murine challenge revealed that \u0394\n                      <jats:italic toggle=\"yes\">hisD<\/jats:italic>\n                      exhibited 5.6-fold higher LD\n                      <jats:sub>50<\/jats:sub>\n                      (4.17 \u00d7 10\n                      <jats:sup>9<\/jats:sup>\n                      CFU\/mL vs. WT 7.42 \u00d7 10\n                      <jats:sup>8<\/jats:sup>\n                      CFU\/mL) and reduced organ colonization (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.05). Through structure-based virtual screening and SPR affinity verification, we discovered pixantrone\u2014a nitrogenated anthraquinone\u2014as a potent HisD inhibitor binding via four hydrogen bonds and two salt bridges. Pixantrone dose-dependently (25\u2013200 \u03bcM) suppressed virulence phenotypes\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , achieving hemolysis inhibition, virulence gene inhibition, and biofilm reduction.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      , pixantrone (30 mg\/kg) decreased serum CRP, IL-6, and TNF-\u03b1 levels while diminishing abscess sizes and splenic bacterial loads (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.05 vs. untreated). These findings establish HisD as a pivotal virulence regulator in\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      through\n                      <jats:italic toggle=\"yes\">saeR\/S<\/jats:italic>\n                      -mediated pathways. Pixantrone demonstrates potent anti-virulence efficacy, positioning HisD inhibition as a promising therapeutic strategy against\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      infections. This study provides foundational insights for developing HisD-targeted agents to combat antibiotic-resistant staphylococcal pathogens.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      The increase in drug-resistant\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      (MRSA) demands therapies that block virulence without promoting resistance. We identify histidinol dehydrogenase (HisD), a histidine-synthesis enzyme, as a key controller of\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      pathogenicity. Disrupting HisD genetically or with pixantrone\u2014a newly identified inhibitor\u2014reduces bacterial toxicity, biofilm formation, and virulence gene activity while improving survival and reducing organ damage in infected mice. Pixantrone's dose-dependent suppression of infection severity and inflammation positions it as a therapeutic candidate. Unlike traditional antibiotics, this strategy disarms bacteria rather than killing them, reducing resistance risks. By uncovering HisD\u2019s role in connecting metabolism to virulence through the\n                      <jats:italic toggle=\"yes\">saeR<\/jats:italic>\n                      \/S system, we reveal a druggable target for fighting multidrug-resistant infections. This work addresses the urgent need for innovative solutions to the global antibiotic resistance crisis, paving the way for therapies that outsmart evolving superbugs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01429-25","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T14:00:48Z","timestamp":1764165648000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Histidinol dehydrogenase (HisD): a critical regulator of\n                    <i>Staphylococcus aureus<\/i>\n                    virulence and a promising target for antivirulence therapy"],"prefix":"10.1128","volume":"14","author":[{"given":"Wenwen","family":"Jiang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01mkqqe32","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory Medicine Center, The Second Hospital & Clinical Medical School, 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