Reading and rewiring natural-product biosynthesis in microbial hosts with genetically encoded biosensors.

Abstract

Covering: 2000 to 2026Natural products (NPs) are structurally diverse bioactive molecules with broad applications in pharmaceuticals, nutraceuticals, cosmetics, and other high-value sectors. Microbial cell factories provide programmable platforms for NP production, but their performance is often constrained by dynamic bottlenecks that are not readily inferred from end-point titers, including limited precursor or cofactor supply, toxic intermediate accumulation, inefficient heterologous enzyme function, and competition with host metabolism. Genetically encoded biosensors translate NP molecules, pathway-relevant metabolites, or cellular states into measurable, selectable, or regulatory outputs. Here, we critically examine biosensor design principles and distinguish the variable detected, recognition modality, output, and implementation format. We then assess how direct product sensing, pathway-state monitoring, dynamic regulation, enzyme screening, genome-wide perturbation, and growth-coupled evolution can support microbial NP engineering. Emphasis is placed on the correspondence between sensor output and the intended engineering objective. This framework clarifies when biosensors can provide actionable information for rewiring NP-producing microbial hosts.

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