Design principles for engineering bacteria to maximise chemical production from batch cultures
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Author(s)
Mannan, Ahmad
Darlington, Alexander
Tanaka, Reiko
Bates, Declan
Type
Journal Article
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 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.
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.
Date Issued
2025-01-02
Date Acceptance
2024-12-09
Citation
Nature Communications, 2025, 16
ISSN
2041-1723
Publisher
Nature Portfolio
Journal / Book Title
Nature Communications
Volume
16
Copyright Statement
© The Author(s) 2024
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.nature.com/articles/s41467-024-55347-y
Publication Status
Published
Article Number
279
Date Publish Online
2025-01-02