Designing an irreversible metabolic switch for scalable induction of microbial chemical production

• Published in: Nature communications Vol. 12; no. 1; pp. 3419 - 11
• Main Authors: Mannan, Ahmad A., Bates, Declan G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/553/2691; 631/553/2695; 631/553/2719; 631/553/552; 631/61/318; Bacteria; Biotechnology; Chemical synthesis; Circuits; Control systems; Control theory; E coli; Escherichia coli - metabolism; Fatty acids; Feedback; Feedback loops; Feedback, Physiological; Homeostasis; Humanities and Social Sciences; Industrial engineering; Manufacturing engineering; Mathematical models; Metabolic Engineering; Metabolism; Microorganisms; multidisciplinary; Nutrients; Oleic Acid - metabolism; Positive feedback; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23606-x

Bacteria can be harnessed to synthesise high-value chemicals. A promising strategy for increasing productivity uses inducible control systems to switch metabolism from growth to chemical synthesis once a large population of cell factories are generated. However, use of expensive chemical inducers limits scalability of this approach for biotechnological applications. Switching using cheap nutrients is an appealing alternative, but their tightly regulated uptake and consumption again limits scalability. Here, using mathematical models of fatty acid uptake in E. coli as an exemplary case study, we unravel how the cell’s native regulation and program of induction can be engineered to minimise inducer usage. We show that integrating positive feedback loops into the circuitry creates an irreversible metabolic switch, which, requiring only temporary induction, drastically reduces inducer usage. Our proposed switch should be widely applicable, irrespective of the product of interest, and brings closer the realization of scalable and sustainable microbial chemical production. A promising strategy to increase product synthesis from bacteria uses inducible systems to switch metabolism to production. Here, the authors use models to show how engineering positive feedback loops into the genetic circuitry creates a switch that requires only temporary induction with a cheap nutrient to switch metabolism irreversibly, and so drastically reduce inducer use and cost.