Autonomous Metabolic Control via Product-Responsive Biosensor for Enhanced Chemical Biosynthesis

Abstract

Efficient microbial production of platform chemicals depends on precise regulation of metabolic fluxes, yet conventional systems rely on external inducers or temperature shifts, limiting real-time adaptability. To address this, we developed a product-responsive dynamic regulation system that autonomously redirects metabolic pathways in response to intracellular product levels, eliminating the need for costly inputs. This system integrates a biosensor that senses the target chemical and modulates key metabolic nodes involved in cofactor regeneration and precursor allocation. Carbon flux is dynamically redirected to enhance reducing power availability, while competing pathways are suppressed during the production phase to maximize precursor flow toward the desired product. The regulation is growth-phase dependent and responds directly to product accumulation. The engineered strain achieved a five-fold increase in product titer compared to the nonregulated control without requiring chemical inducers or temperature modulation. This study demonstrates the potential of biosensor-guided dynamic regulation as a robust and scalable strategy for improving microbial chemical biosynthesis under industrially relevant conditions.