Targeted Discovery and Characterization of Type‐II PKS‐NRPS Hybrid DNA‐Alkylating Antibiotics
Abstract
Abstract DNA alkylating natural products usually exhibit diverse bioactivity and serve as a crucial source of drug leads. Here, we employed genome mining guided by HTH‐42 superfamily resistance gene to precisely discover a new class of DNA‐alkylating antibiotics, xinghaicarcins, from Streptomyces xinghaiensis . They possess an intricate spiro‐epoxide‐bearing spiroketal heptacyclic scaffold fused with a pipecolic acid, assembled by a type II polyketide synthase–nonribosomal peptide synthetase hybrid system. An aminotransferase XhnB1 and a methyltransferase XhnM are identified to catalyze the formation of N‐methylated pipecolic acid building block, leading to the completion of the polyketide–peptide backbone. The identification of XhnM facilitated stereochemical determination of six chiral centers in xinghaicarcins by co‐crystallization. Notably, xinghaicarcins exhibit potent antibacterial activity against drug‐resistant pathogens and cytotoxicity against multiple cancer cell lines. Additionally, the HTH‐42 superfamily resistant protein, XhnU2, was characterized to mitigate xinghaicarcin‐induced genotoxicity. This work provides comprehensive insights into structure, biosynthesis, bioactivity, and self‐resistance mechanisms of xinghaicarcins, expanding diversity of DNA alkylating natural products.
Article Details
Authors (14)
Qiu‐Yue Nie
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200032 China
Shi‐Qi Fang
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200032 China
Lian Wu
Ruo‐Qin Gao
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200032 China
Yu Hu
Dian Ding
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200032 China
Hai‐Xue Pan
Key Laboratory of Glyco‐drug Research of Zhejiang Province School of Chemistry and Materials Science Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences Hangzhou China
Zeng‐Fei Pei
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200032 China
Jun‐Bin He
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200032 China
Qiang Zhou
Zi‐Hui Chen
Key Laboratory of Glyco‐drug Research of Zhejiang Province School of Chemistry and Materials Science Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences Hangzhou China
Xian‐Feng Hou
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200032 China
Xin‐Qing Zhao
State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology Shanghai Jiao Tong University Shanghai 200240 China
Gong‐Li Tang
Key Laboratory of Glyco‐drug Research of Zhejiang Province School of Chemistry and Materials Science Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences Hangzhou China