Discovery and Biosynthesis of Celluxanthenes, Antibacterial Arylpolyene Alkaloids from Diverse Cellulose‐Degrading Anaerobic Bacteria

Cellulose degradation by anaerobic bacteria plays an eminent role in the global carbon cycle and is a critical step in biofuel production. The anaerobe thermophile Clostridium thermocellum (now: Acetivibrio thermocellus) is particularly efficient at breaking down biomass and produces a 'yellow affinity substance' (YAS), a pigment that has been implicated in signaling and conferring a higher affinity of the cellulosome to YAS‐loaded cellulose. However, despite its importance, the nature and biosynthetic origin of YAS have remained elusive. Here we show by isolation and structure elucidation that YAS is a complex of unusual arylpolyene alkaloids (celluxanthenes). Stable isotope labeling experiments reveal all biosynthetic building blocks for celluxanthene assembly. Through a targeted gene deletion, we identify the celluxanthene (cex) biosynthesis gene cluster and propose a biosynthetic model in which an arylpolyene generated by an iterative type I polyketide synthase (PKS) undergoes a head‐to‐head fusion with a tryptophan‐derived ketoacid to form a tetronate. Genome mining and metabolic profiling revealed that diverse cellulolytic anaerobes harbor cex gene loci and produce celluxanthene congeners. Celluxanthenes show antibiotic activity against Gram‐positive bacteria. This study work solves the long‐standing enigma surrounding the nature of YAS, establishes bioengineering approaches, and helps elucidating the biological roles of these intricate pigments.