Natural products remain a major source of antibiotics, but discovery efforts have traditionally treated biosynthetic gene clusters as sources of individual bioactive molecules1–5. Increasing evidence has suggested that microorganisms can instead encode coordinated multi-metabolite systems, yet the genetic architectures and biological logic of such systems remain poorly understood6–12. Here we show that Streptomyces spp. encode a highly conserved biosynthetic megacluster that produces four structurally distinct natural product families—stravidins, acidomycin, dapamycins, and 2-methyl-7-keto-8-aminopelargonic acid (α-Me-KAPA)—alongside the biotin-binding protein streptavidin. These components converge on bacterial biotin metabolism through complementary mechanisms, including enzyme inhibition, prodrug activation, cofactor mimicry and biotin sequestration. The encoded metabolites are co-produced and act synergistically across Gram-negative and mycobacterial species, with stravidin S2 and α-Me-KAPA showing enhanced efficacy in combination in a mouse model of multidrug-resistant Escherichia coli infection. This megacluster reveals a genetically encoded chemical arsenal that functions as a naturally evolved combination therapy against a conserved metabolic pathway. More broadly, our findings suggest that higher-order biosynthetic architectures may represent an overlooked reservoir of antibiotic mechanisms and support a shift from discovering isolated natural products to reconstructing native synergistic systems.
