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Caseinolytic peptidase P (ClpP), a central virulence regulator in MRSA, represents an attractive yet underexploited target. Here, we developed a discovery platform integrating self\u2010resistance gene\u2010guided genome mining with dual functional screening, combining fluorometric\u2010based assay and counter\u2010screening against ADEP\u2010induced ClpP activation. This led to the discovery of streptoclipamides A\u2013G, novel hybrid polyketide\u2010nonribosomal peptide ClpP inhibitors from\n                    <jats:italic>str<\/jats:italic>\n                    BGC, validated via heterologous expression and gene knockout. Structure\u2013activity relationship studies enabled by engineered analogues identified key pharmacophores. Streptoclipamide A potently inhibits ClpP (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u00a0=\u00a0480\u00a0nM) by engaging Thr72 via its C\u201021 hydroxyl group, confirmed by biophysics and self\u2010resistance\u2010conferring T72P mutation. Streptoclipamide A suppressed MRSA virulence in vitro by reducing critical toxin production, including \u03b1\u2010hemolysin, and demonstrated protection in\n                    <jats:italic>Galleria mellonella<\/jats:italic>\n                    and murine pneumonia models. This work expands chemical diversity of ClpP\u2010targeting agents, and establishes a genome mining\u2010driven platform for discovering new therapeutics against antibiotic\u2010resistant pathogens.\n                  <\/jats:p>","DOI":"10.1002\/anie.202514683","type":"journal-article","created":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T12:04:39Z","timestamp":1759579479000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Discovery of Antivirulence ClpP Inhibitors by Self\u2010Resistance Gene\u2010Guided Mining Coupled with Dual Functional Screening"],"prefix":"10.1002","volume":"64","author":[{"given":"Yongchao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine Zhongnan Hospital of Wuhan University TaiKang Center for Life and Medical Sciences School of Pharmaceutical Sciences Wuhan University  Wuhan 430071 P.R. 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