Engineered microbes often suffer from reduced fitness resulting from metabolic burden and various stresses. The productive lifetime of a bioreactor with engineered microbes is therefore susceptible to the rise of nonproductive mutants with better fitness. Synthetic addiction is emerging as a concept to artificially couple the growth rate of the microbe to production to tackle this problem. However, only a few successful cases of synthetic addiction systems have been reported to date. To understand the limitations and design constraints in long-term cultivations, we designed and studied conditional synthetic addiction circuits in Saccharomyces cerevisiae. This allowed us to probe a range of selective pressure strengths and identify the optimal balance between circuit stability and production-to-growth coupling. In the optimal balance, the productive lifetime was greatly extended compared with suboptimal circuit tuning. With a too-high or -low pressure, we found that production declines mainly through homologous recombination. These principles of trade-off in the design of synthetic addition systems should lead to the better control of bioprocess performance.

• PMID: 34699715
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Journal Article | Research Support, Non-U.S. Gov't

Authors

Lee SW, Rugbjerg P, Sommer MOA

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