Genome mining for macrolactam-encoding gene clusters allowed for the network-guided isolation of β-amino acid-containing cyclic derivatives and heterologous production of ciromicin A

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β-Amino acid-containing macrolactams represent a structurally diverse group of bioactive natural products derived from polyketides; however we are currently lacking a comprehensive overview about their abundance across bacterial families and the underlying biosynthetic diversity. In this study, we employed a targeted β-amino acid-specific homology-based multi-query search to identify potential bacterial macrolactam producers. Here we demonstrate that approximately 10% of each of the identified actinobacterial genera harbor a biosynthetic gene cluster (BGC) encoding macrolactam production. Based on our comparative study, we propose that mutations occurring in specific regions of polyketide synthases (PKS) are the primary drivers behind the variation in macrolactam ring sizes. We successfully validated two producers of ciromicin A from the genus Amycolatopsis, revised the composition of the biosynthetic gene cluster region mte of macrotermycins, and confirmed the ciromicin biosynthetic pathway through heterologous expression. Additionally, network-based metabolomic analysis uncovered three previously unreported macrotermycin congeners from Amycolatopsis sp. M39. The combination of targeted mining and network-based analysis serves as a powerful tool for identifying macrolactam producers and our studies will catalyze the future discovery of yet unreported macrolactams.

OriginalsprogEngelsk
Artikelnummer257
TidsskriftCommunications Chemistry
Vol/bind6
Antal sider15
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
This study was funded by the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) under Project-ID 239748522 – CRC 1127 (project A6). We are grateful for the financial support from the Agence Nationale de la Recherche (ANR, ANR-17-CE07-0051-01) and the German Research Foundation (DFG, BE 4799/3-1). This work was also supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT; grant numbers 2019R1A5A2027340, 2021R1A2C2007937, and 2021R1I1A1A0104960613) and the European Research Council (ERC-CoG 771349). K.A.J. and K.H.B were supported by the Villum Foundation (Young Investigator Programme, project no. 15560) and the Carlsberg Foundation (Distinguished Associate Professor Fellowship, project no. CF17- 0248). We also thank staff and field assistants from the Binatang Research Center and local communities in Yawan, as well as the Conservation and Environment Protection Authority (CEPA) of Papua New Guinea for assistance with research permits and export permits.

Funding Information:
This study was funded by the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) under Project-ID 239748522 – CRC 1127 (project A6). We are grateful for the financial support from the Agence Nationale de la Recherche (ANR, ANR-17-CE07-0051-01) and the German Research Foundation (DFG, BE 4799/3-1). This work was also supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT; grant numbers 2019R1A5A2027340, 2021R1A2C2007937, and 2021R1I1A1A0104960613) and the European Research Council (ERC-CoG 771349). K.A.J. and K.H.B were supported by the Villum Foundation (Young Investigator Programme, project no. 15560) and the Carlsberg Foundation (Distinguished Associate Professor Fellowship, project no. CF17- 0248). We also thank staff and field assistants from the Binatang Research Center and local communities in Yawan, as well as the Conservation and Environment Protection Authority (CEPA) of Papua New Guinea for assistance with research permits and export permits.

Publisher Copyright:
© 2023, The Author(s).

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