Acyl amides derived from a bacterial symbiont control development of its nematode host

Symbiotic bacteria frequently regulate host development through small-molecule signals. In the entomopathogenic Steinernema nematode - Xenorhabdus bacterium symbiosis, which is widely used in biological pest control, the signals that trigger nematode development have remained unknown. Using a phenotypic screen of Xenorhabdus mutants, we identified bacterial acyl amides, which we named stripteamides, as signals required for efficient recovery of Steinernema infective juveniles. Stripteamides are synthesized from phenylethylamine and activated fatty acid substrates by StaS, a previously uncharacterized amide synthase. Mechanistic and structural analyses indicate that StaS evolved from the initiation module of a nonribosomal peptide synthetase (NRPS) and was repurposed to generate signaling metabolites for host development. Stripteamide signaling is conserved across Xenorhabdus species and operates in different Steinernema hosts. These findings reveal a new function for widespread bacterial acyl amides that previously have been shown as cytotoxic and affecting bacterial quorum sensing, highlighting the context dependence of microbial natural product language.