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

Abstract

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 in a cell to maximise volumetric productivity and yield from batch cultures. Our results suggest that selecting strains in the lab for maximum growth and product synthesis can achieve close to maximum culture productivity and yield, but the growth-synthesis trade-off fundamentally 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 optimal 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.