Design principles for engineering bacteria to maximise chemical production from batch cultures

• Published in: Nature communications Vol. 16; no. 1; pp. 279 - 10
• Main Authors: Mannan, Ahmad A., Darlington, Alexander P. S., Tanaka, Reiko J., Bates, Declan G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.01.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/553/552; 631/61/318; Bacteria; Bacteria - genetics; Bacteria - metabolism; Batch Cell Culture Techniques; Chemical synthesis; Circuits; Design; Engineering; Escherichia coli - genetics; Escherichia coli - growth & development; Escherichia coli - metabolism; Factories; Gene expression; Gene Expression Regulation, Bacterial; Gene Regulatory Networks; Genetic analysis; Humanities and Social Sciences; Industrial engineering; Metabolic engineering; Metabolic Engineering - methods; Microorganisms; multidisciplinary; Performance enhancement; Population genetics; Productivity; Science; Science (multidisciplinary); Topology; Tradeoffs
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-55347-y

Bacteria can be engineered to manufacture chemicals, but it is unclear how to optimally engineer a single cell to maximise production performance from batch cultures. Moreover, the performance of engineered production pathways is affected by competition for the host’s native resources. Here, using a ‘host-aware’ computational framework which captures competition for both metabolic and gene expression resources, we uncover design principles for engineering the expression of host and production enzymes at the cell level which maximise volumetric productivity and yield from batch cultures. However, this does not break the fundamental growth-synthesis trade-off which limits production performance. We show that engineering genetic circuits to switch cells to a high synthesis-low growth state after first growing to a large population can further improve performance. By analysing different circuit topologies, we show that highest performance is achieved by circuits that inhibit host metabolism to redirect it to product synthesis. Our results should facilitate construction of microbial cell factories with high and efficient production capabilities. Engineering microbial cell factories for chemical manufacture remains challenging due to trade-offs between production and growth. Here, the authors uncover how to design genetic circuits in bacteria that maximise volumetric productivity and yield.