A spider-transmitted fungus (Rhizopus microsporus) that was isolated from necrotic human tissue was found to harbor endofungal bacteria (Burkholderia sp.). Metabolic profiling of the symbionts revealed a complex of cytotoxic agents (necroximes). Their structures were fully characterized as oxime-substituted benzolactone enamides equipped with a peptidic side chain. Necroximes are potent cytotoxic agents that are also formed in symbiosis with the fungal host and could have contributed to the necrosis. Genome sequencing and in silico analyses revealed a novel modular PKS/NRPS assembly line equipped with several non-canonical domains. Based on gene deletion mutants, we propose the first biosynthetic model for bacterial benzolactones. We identified specific traits that serve as genetic handles to identify related salicylate macrolide pathways in various other bacterial genera (lobatamide, oximidine, apicularen and cruentaren). Our work sets an unusual example of hypothesis-based drug discovery in the context of human disease. Knowledge on the biosynthetic pathway initiates biosynthetic engineering and genome-mining approaches.