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<p>Lariat-shaped lipopeptides are important antimicrobial agents; however, their complex structures pose synthetic challenges that hamper efficient structural diversification. Here we report a new chemoenzymatic approach that facilitates access to lariat-shaped macrocycles. Unprotected, branched peptides bearing multiple nucleophiles, including a native amino terminus and a pseudo-amino terminus, were site-selectively cyclized using versatile non-ribosomal peptide cyclases, generating an array of lariat peptides with diverse sequences and ring sizes. The generality of this strategy was demonstrated using two penicillin-binding protein-type thioesterases, SurE and WolJ, as well as one type-I thioesterase, TycC thioesterase. Furthermore, the remaining nucleophile, which was not involved in the cyclization process, was exploited as a reactive handle for subsequent diversification via a site-selective acylation reaction (that is, Ser/Thr ligation). The tandem cyclization–acylation strategy enabled the one-pot, modular synthesis of lariat-shaped lipopeptides equipped with various acyl groups. Biological screening revealed that the site-selective acylation endowed the macrocyclic scaffolds with antimycobacterial activity and led to the identification of lipopeptides that inhibit 50% of growth at concentrations of 8–16 µg ml<sup>−1</sup>.</p><p></p>

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Non-ribosomal peptide cyclase-directed chemoenzymatic synthesis of lariat lipopeptides

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月4日

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  • Masakazu Kobayashi,
  • Kenichi Matsuda,
  • Yuito Yamada,
  • Rintaro Ichihara,
  • Naho Onozawa,
  • Hanako Fukano,
  • Yoshihiko Hoshino,
  • Aki Hirabayashi,
  • Masato Suzuki,
  • Akira Katsuyama,
  • Satoshi Ichikawa,
  • Toshiyuki Wakimoto

摘要

Lariat-shaped lipopeptides are important antimicrobial agents; however, their complex structures pose synthetic challenges that hamper efficient structural diversification. Here we report a new chemoenzymatic approach that facilitates access to lariat-shaped macrocycles. Unprotected, branched peptides bearing multiple nucleophiles, including a native amino terminus and a pseudo-amino terminus, were site-selectively cyclized using versatile non-ribosomal peptide cyclases, generating an array of lariat peptides with diverse sequences and ring sizes. The generality of this strategy was demonstrated using two penicillin-binding protein-type thioesterases, SurE and WolJ, as well as one type-I thioesterase, TycC thioesterase. Furthermore, the remaining nucleophile, which was not involved in the cyclization process, was exploited as a reactive handle for subsequent diversification via a site-selective acylation reaction (that is, Ser/Thr ligation). The tandem cyclization–acylation strategy enabled the one-pot, modular synthesis of lariat-shaped lipopeptides equipped with various acyl groups. Biological screening revealed that the site-selective acylation endowed the macrocyclic scaffolds with antimycobacterial activity and led to the identification of lipopeptides that inhibit 50% of growth at concentrations of 8–16 µg ml−1.