Authors
Masakazu Kobayashi, Kenichi Matsuda, Yuito Yamada, Rintaro Ichihara, Naho Onozawa, Hanako Fukano, Yoshihiko Hoshino, Aki Hirabayashi, Masato Suzuki, Akira Katsuyama, Satoshi Ichikawa, Toshiyuki Wakimoto
Published in
Nature chemistry. Nov 04, 2025. Epub Nov 04, 2025.
Abstract
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.
PMID:
41188574
Bibliographic data and abstract were imported from PubMed on 05 Nov 2025.
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