Journal article

Mining Symbionts of a Spider-Transmitted Fungus Illuminates Uncharted Biosynthetic Pathways to Cytotoxic Benzolactones

Sarah P Niehs, Benjamin Dose, Sophie Richter, Sacha J Pidot, Hans-Martin Dahse, Timothy P Stinear, Christian Hertweck

Angewandte Chemie International Edition | WILEY-V C H VERLAG GMBH | Published : 2020

Abstract

A spider-transmitted fungus (Rhizopus microsporus) that was isolated from necrotic human tissue was found to harbor endofungal bacteria (Burkholderia sp.). Metabolic profiling of the symbionts revealed a complex of cytotoxic agents (necroximes). Their structures were characterized as oxime-substituted benzolactone enamides with a peptidic side chain. The potently cytotoxic necroximes are also formed in symbiosis with the fungal host and could have contributed to the necrosis. Genome sequencing and computational analyses revealed a novel modular PKS/NRPS assembly line equipped with several non-canonical domains. Based on gene-deletion mutants, we propose a biosynthetic model for bacterial ben..

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Grants

Awarded by DFG


Funding Acknowledgements

We thank H. Heinecke for NMR, A. Perner for MS/MS measurements, C. Weigel for bioactivity assays, E.-M. Neumann for assistance in cytotoxicity assays and A. Hartmann for technical assistance. Assistance by Dr. Z. Uzum and helpful discussions with R. Hermenau and Dr. K. Dunbar are gratefully acknowledged. This work was financially supported by the DFG (SFB 1127, ChemBioSys, and Leibniz Prize).