Extracellularly oxidative activation and inactivation of matured prodrug for cryptic self-resistance in naphthyridinomycin biosynthesis

文献类型： 外文期刊

第一作者： Zhang, Yue

作者： Zhang, Yue;Wen, Wan-Hong;Pu, Jin-Yue;Tang, Man-Cheng;Tang, Gong-Li;Zhang, Liwen;Xu, Yuquan;Peng, Chao

作者机构：

关键词： self-protection; secreted enzyme; tetrahydroisoquinoline alkaloids; warhead; natural product biosynthesis

期刊名称：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA （ 影响因子：11.205； 五年影响因子：12.291 ）

ISSN： 0027-8424

年卷期： 2018 年 115 卷 44 期

页码：

收录情况： SCI

摘要： Understanding how antibiotic-producing bacteria deal with highly reactive chemicals will ultimately guide therapeutic strategies to combat the increasing clinical resistance crisis. Here, we uncovered a distinctive self-defense strategy featured by a secreted oxidoreductase NapU to perform extracellularly oxidative activation and conditionally overoxidative inactivation of a matured prodrug in naphthyridinomycin (NDM) biosynthesis from Streptomyces lusitanus NRRL 8034. It was suggested that formation of NDM first involves a nonribosomal peptide synthetase assembly line to generate a prodrug. After exclusion and prodrug maturation, we identified a pharmacophore-inactivated intermediate, which required reactivation by NapU via oxidative C-H bond functionalization extracellularly to afford NDM. Beyond that, NapU could further oxidatively inactivate the NDM pharmacophore to avoid self-cytotoxicity if they coexist longer than necessary. This discovery represents an amalgamation of sophisticatedly temporal and spatial shielding mode conferring self-resistance in antibiotic biosynthesis from Gram-positive bacteria.

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