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 generate natural products to mediate bacteria–nematode–insect interactions. However, a lack of systematic analysis of the XP biosynthetic gene clusters (BGCs) has limited the understanding of how natural products affect interactions between the organisms. Here we combine pangenome and sequence similarity networks to analyse BGCs from 45 XP strains that cover all sequenced strains in our collection and represent almost all XP taxonomy. The identified 1,000 BGCs belong to 176 families. The most conserved families are denoted by 11 BGC classes. We homologously (over)express the ubiquitous and unique BGCs and identify compounds featuring unusual architectures. The bioactivity evaluation demonstrates that the prevalent compounds are eukaryotic proteasome inhibitors, virulence factors against insects, metallophores and insect immunosuppressants. These findings explain the functional basis of bacterial natural products in this tripartite relationship.

微生物有助于真核宿主的生物学和生理学，并通过天然产物影响其他生物。Xenorhabdus和Photorhabdus ( XP ) 与昆虫病原线虫共生共生，产生天然产物来介导细菌-线虫-昆虫相互作用。然而，缺乏对XP生物合成基因簇 (BGC)的系统分析限制了对天然产物如何影响生物体之间相互作用的理解。在这里，我们结合泛基因组和序列相似性网络来分析来自 45 个XP菌株的 BGC，这些菌株涵盖了我们集合中的所有测序菌株并代表了几乎所有XP分类。已确定的 1,000 个 BGC 属于 176 个家族。最保守的家族由 11 个 BGC 类别表示。我们同源（过度）表达普遍存在且独特的 BGC，并识别出具有不寻常结构的化合物。生物活性评估表明，普遍存在的化合物是真核蛋白酶体抑制剂、昆虫毒力因子、金属载体和昆虫免疫抑制剂。这些发现解释了细菌天然产物在这种三方关系中的功能基础。