Global analysis of biosynthetic gene clusters reveals conserved and unique natural products in entomopathogenic nematode-symbiotic bacteria

Microorganisms contribute to the biology and physiology of eukaryotic hosts and affect other organisms through natural products. Xenorhabdus and Photorhabdus ( XP ) living in mutualistic symbiosis with entomopathogenic nematodes produce a myriad of natural products to mediate bacteria–nematode–insect interactions. However, a lack of systematic analysis of the biosynthetic gene clusters (BGCs) has limited the understanding of how natural products justify the bacterial niche specificity. Here we combine pangenome and sequence similarity networks to analyze BGCs from 45 XP species. The identified 1,000 BGCs belong to 176 families, over half of which are unknown. Eleven BGCs represent the most conserved families. We then homologously express the ubiquitous and unique BGCs and identify compounds featuring unusual architectures. The bioactivity evaluation demonstrates that the prevalent compounds are eukaryotic proteasome inhibitors, insect virulence factors, or insect immune suppressors. These findings account for the functional basis of bacterial natural products in this tripartite relationship. ### Competing Interest Statement Y.-M.S., W.K., M.G., and H.B.B. are inventors on a patent application covering the structure and use of IOC, which has been filed by Max Planck Society, Technical University of Munich, and Goethe University Frankfurt. Y.-M.S., D.A., J.J.C., and H.B.B. are inventors on a patent application covering the structure and use of rhabdobranin, which has been filed by Max Planck Society. The other authors declare no competing interests.