Mining Symbionts of a Spider‐Transmitted Fungus Illuminates Uncharted Biosynthetic Pathways to Cytotoxic Benzolactones. Issue 20 (18th March 2020)

• Record Type: Journal Article
• Authors: Niehs, Sarah P.; Dose, Benjamin; Richter, Sophie; Pidot, Sacha J.; Dahse, Hans‐Martin; Stinear, Timothy P.; Hertweck, Christian
• Is Part Of: Angewandte Chemie international edition. Volume 59:Issue 20(2020)
• Page Start: 7766
• Page End: 7771
• Publication Date: 2020-03-18
• Subjects: biosynthesis -- drug discovery -- genome mining -- natural products -- symbiosis; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201916007
• Languages: English
• ISSNs: 1433-7851

Abstract

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 benzolactones. We identified specific traits that serve as genetic handles to find related salicylate macrolide pathways (lobatamide, oximidine, apicularen) in various other bacterial genera. Knowledge of the biosynthetic pathway enables biosynthetic engineering and genome‐mining approaches. Abstract : Spider sense : The fungus Rhizopus microsporus, isolated from necrotic tissue resulting from a spider bite, was found to contain bacteria ( Burkholderia sp.) that produce a complex of highly cytotoxic compounds (necroximes). Analysis of the PKS/NRPS hybrid assembly line and genome mining revealed the molecular basis of the biosynthesis of V‐ATPase‐inhibiting antitumor agents from diverse biological origins.