6533b7d4fe1ef96bd1263424

RESEARCH PRODUCT

Insect-associated bacteria assemble the antifungal butenolide gladiofungin by non-canonical polyketide chain termination

Keishi IshidaSarah P. NiehsBenjamin DoseMartin KaltenpothLaura V. FlórezChristian HertweckChristian HertweckRory F. LittleJana Kumpfmüller

subject

Burkholderia gladioliAntifungal AgentsBurkholderianatural productsantifungal compoundsMicrobial Sensitivity TestsBiosynthesis010402 general chemistry01 natural sciencesCatalysisPurpureocillium lilacinumPolyketide4-ButyrolactonePolyketide synthasegenome miningGene clusterAnimalsButenolidebiology010405 organic chemistryCommunicationGeneral Chemistrybiology.organism_classificationCommunications0104 chemical sciencesColeopteraBiochemistryPolyketidesHypocrealesbiology.proteinLactimidomycinPharmacophore

description

Abstract Genome mining of one of the protective symbionts (Burkholderia gladioli) of the invasive beetle Lagria villosa revealed a cryptic gene cluster that codes for the biosynthesis of a novel antifungal polyketide with a glutarimide pharmacophore. Targeted gene inactivation, metabolic profiling, and bioassays led to the discovery of the gladiofungins as previously‐overlooked components of the antimicrobial armory of the beetle symbiont, which are highly active against the entomopathogenic fungus Purpureocillium lilacinum. By mutational analyses, isotope labeling, and computational analyses of the modular polyketide synthase, we found that the rare butenolide moiety of gladiofungins derives from an unprecedented polyketide chain termination reaction involving a glycerol‐derived C3 building block. The key role of an A‐factor synthase (AfsA)‐like offloading domain was corroborated by CRISPR‐Cas‐mediated gene editing, which facilitated precise excision within a PKS domain.

10.1002/anie.202005711https://hdl.handle.net/21.11116/0000-0007-E5C1-C21.11116/0000-0007-E678-F21.11116/0000-0007-E67E-9