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Herein, we describe the discovery of Py\u201027, a pyrazole\u2010derived compound exhibiting potent bactericidal activity against MRSA. A chemoproteomic approach identified aspartate transcarbamoylase (ATCase), a key enzyme in\n                    <jats:italic>de novo<\/jats:italic>\n                    pyrimidine synthesis, as the specific target of Py\u201027. Biophysical and enzymatic assays confirmed its high\u2010affinity binding and inhibition of ATCase, while genetic knockout established ATCase as a druggable metabolic vulnerability in MRSA. Mechanistically, Py\u201027 disrupts pyrimidine synthesis, thereby impairing DNA replication, perturbing metabolic homeostasis, and ultimately inducing lethal oxidative damage. Notably, Py\u201027 eradicates mature biofilms while exhibiting a low resistance propensity and favorable toxicological profiles. In animal infection models, Py\u201027 demonstrated superior in vivo efficacy compared to vancomycin and promoted infection resolution and tissue repair. This study demonstrates the potential of pyrazole\u2010amide compounds targeting ATCase for the treatment of MRSA infections.\n                  <\/jats:p>","DOI":"10.1002\/advs.76704","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:20:51Z","timestamp":1784550051000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pyrazole\u2010Derived Antibacterial Compounds Effectively Treat Methicillin\u2010Resistant\n                    <i>Staphylococcus Aureus<\/i>\n                    Infections by Inhibiting Aspartate Transcarbamoylase"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1275-304X","authenticated-orcid":false,"given":"Xiaorong","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of New Animal Drug Project Lanzhou Institute of Husbandry and Pharmaceutical Sciences Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture Chinese Academy of Agricultural Sciences  Lanzhou Gansu P. 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