A tRNA‐Gated Cyclodepsipeptide Pathway Produces a Chemical Effector That Disarms Bacterial Development

Bacteria compete not only by killing rivals but also by disrupting their developmental programs, yet the molecular basis of such nonlethal interference remains largely unknown. Here, we report tamastrepamides, a family of alkylproline‐containing cyclodepsipeptides from Streptomyces sp. HL19 that function as interspecific effectors by selectively downregulating transcription of the master developmental regulator bldD . The horizontally acquired tam biosynthetic gene cluster is conspicuously enriched in rare TTA codons, functionally coupling its expression to the developmentally regulated tRNA Leu (UAA) encoded by bldA . Tamastrepamide A arrests sporulation and diminishes secondary metabolite production in diverse actinomycetes without inhibiting vegetative growth, thereby chemically phenocopying a Δ bldD mutant. Promoter‐specific reporter assays demonstrate that tamastrepamide A reduces bldD promoter activity, while the producer strain is intrinsically insensitive to this effect. Production of tamastrepamides strictly depends on the functionally specialized tRNA Leu (UAA), revealing a self‐contained regulatory circuit in which a developmentally gated metabolite disables the same developmental program in neighboring competitors. These findings illustrate an ecological strategy in which a developmentally regulated biosynthetic pathway produces a diffusible metabolite that interferes with the sporulation program of competing actinomycetes.