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Here, we employed genome mining guided by HTH\u201042 superfamily resistance gene to precisely discover a new class of DNA\u2010alkylating antibiotics, xinghaicarcins, from\n                    <jats:italic>Streptomyces xinghaiensis<\/jats:italic>\n                    . They possess an intricate spiro\u2010epoxide\u2010bearing spiroketal heptacyclic scaffold fused with a pipecolic acid, assembled by a type II polyketide synthase\u2013nonribosomal peptide synthetase hybrid system. An aminotransferase XhnB1 and a methyltransferase XhnM are identified to catalyze the formation of N\u2010methylated pipecolic acid building block, leading to the completion of the polyketide\u2013peptide backbone. The identification of XhnM facilitated stereochemical determination of six chiral centers in xinghaicarcins by co\u2010crystallization. Notably, xinghaicarcins exhibit potent antibacterial activity against drug\u2010resistant pathogens and cytotoxicity against multiple cancer cell lines. Additionally, the HTH\u201042 superfamily resistant protein, XhnU2, was characterized to mitigate xinghaicarcin\u2010induced genotoxicity. This work provides comprehensive insights into structure, biosynthesis, bioactivity, and self\u2010resistance mechanisms of xinghaicarcins, expanding diversity of DNA alkylating natural products.\n                  <\/jats:p>","DOI":"10.1002\/anie.202512820","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T08:00:51Z","timestamp":1754380851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Targeted Discovery and Characterization of Type\u2010II PKS\u2010NRPS Hybrid DNA\u2010Alkylating Antibiotics"],"prefix":"10.1002","volume":"64","author":[{"given":"Qiu\u2010Yue","family":"Nie","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences Chinese Academy of Sciences  Shanghai 200032 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