Mannan Ahmad A, Darlington Alexander P S, Tanaka Reiko J, Bates Declan G
Department of Bioengineering, Imperial College London, London, UK.
Warwick Integrative Synthetic Biology Centre, School of Engineering, University of Warwick, Coventry, UK.
Nat Commun. 2025 Jan 2;16(1):279. 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.
细菌可以通过工程改造来制造化学品，但目前尚不清楚如何对单个细胞进行优化工程设计，以实现分批培养生产性能的最大化。此外，工程化生产途径的性能会受到宿主天然资源竞争的影响。在此，我们使用一个“宿主感知”计算框架，该框架考虑了代谢资源和基因表达资源的竞争，从而揭示了在细胞水平上设计宿主酶和生产酶表达的原则，这些原则能够使分批培养的体积生产率和产量最大化。然而，这并没有打破限制生产性能的基本生长 - 合成权衡。我们表明，在细胞首先生长到大量群体后，设计遗传回路将细胞切换到高合成 - 低生长状态可以进一步提高性能。通过分析不同的回路拓扑结构，我们发现抑制宿主代谢以将其重定向到产物合成的回路能够实现最高性能。我们的研究结果应有助于构建具有高效生产能力的微生物细胞工厂。
