Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States.
Center for Quantitative Biodesign, Duke University, Durham, North Carolina 27708, United States.
ACS Synth Biol. 2024 Apr 19;13(4):1142-1151. doi: 10.1021/acssynbio.3c00615. Epub 2024 Apr 3.
The metabolic engineering of microbes has broad applications, including biomanufacturing, bioprocessing, and environmental remediation. The introduction of a complex, multistep pathway often imposes a substantial metabolic burden on the host cell, restraining the accumulation of productive biomass and limiting pathway efficiency. One strategy to alleviate metabolic burden is the division of labor (DOL) in which different subpopulations carry out different parts of the pathway and work together to convert a substrate into a final product. However, the maintenance of different engineered subpopulations is challenging due to competition and convoluted interstrain population dynamics. Through modeling, we show that dynamic division of labor (DDOL), which we define as the DOL between indiscrete populations capable of dynamic and reversible interchange, can overcome these limitations and enable the robust maintenance of burdensome, multistep pathways. We propose that DDOL can be mediated by horizontal gene transfer (HGT) and use plasmid genomics to uncover evidence that DDOL is a strategy utilized by natural microbial communities. Our work suggests that bioengineers can harness HGT to stabilize synthetic metabolic pathways in microbial communities, enabling the development of robust engineered systems for deployment in a variety of contexts.
微生物代谢工程具有广泛的应用，包括生物制造、生物加工和环境修复。引入复杂的多步途径通常会给宿主细胞带来很大的代谢负担，限制了生产性生物质的积累，并限制了途径效率。减轻代谢负担的一种策略是分工（DOL），其中不同的亚群执行途径的不同部分，并共同努力将底物转化为最终产物。然而，由于竞争和复杂的菌株间种群动态，维持不同的工程亚群是具有挑战性的。通过建模，我们表明，动态分工（DDOL），即我们定义为能够进行动态和可逆交换的不连续种群之间的分工，可以克服这些限制，并能够稳健地维持繁琐的多步途径。我们提出，DDOL 可以通过水平基因转移（HGT）介导，并利用质粒基因组学来揭示 DDOL 是自然微生物群落利用的一种策略的证据。我们的工作表明，生物工程师可以利用 HGT 来稳定微生物群落中的合成代谢途径，从而为在各种情况下部署的稳健工程系统的发展提供了可能。
