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Abstract Microbial biosynthetic gene clusters (BGCs) encode diverse bioactive molecules but remain mostly silent under lab conditions, reflecting a balance between regulatory control and the metabolic cost of secondary metabolite production. While activation strategies exist, the yields stay low because switching on a cluster doesn’t guarantee the host can sustain biosynthesis. This review covers the regulatory architecture and metabolic constraints, including precursor availability, energy status, and nutrient sensing, that shape BGC output. We argue that coupling regulatory network models with genome-scale metabolic models offers a powerful framework for unlocking silent BGCs and realising the full biosynthetic potential within microbial genomes.
Matine et al. (Fri,) studied this question.