Barceloneic acid A enables Metarhizium robertsii to establish parasitism in insects and mutualism in plants by inhibiting farnesyltransferase

Many microbial symbionts form distinct partnerships with different hosts. While the mechanisms specific to each partnership are well understood, the shared strategies that a symbiont uses to interact with disparate hosts remain understudied. Here, we report that the endophytic and entomopathogenic fungus Metarhizium robertsii deploys the farnesyltransferase inhibitor barceloneic acid A (BA-A) to modulate the physiology of insects and plants to develop parasitism and mutualism, respectively. During insect infection, BA-A inhibits host Ras protein farnesylation, reducing its cell membrane localization and suppressing MAPK/ERK phosphorylation and production of the hormone 20-hydroxyecdysone. This suppresses larval pupation and decelerates larval death by upregulating antibacterial peptides to kill gut-derived opportunistic pathogens in the hemocoel, prolonging M. robertsii ’s access to nutrient-rich larval hemolymph for maximal reproduction. BA-A also inhibits the plant farnesyltransferase, downregulating the defense-related protein PR2 to facilitate mutualism development. The BA-A biosynthetic gene cluster was characterized, which is activated during interactions with insects and plants.