Exploring Selective Pressure Trade-Offs for Synthetic Addiction to Extend Metabolite Productive Lifetimes in Yeast

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Abstract

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.
Original languageEnglish
JournalACS Synthetic Biology
Volume10
Issue number11
Pages (from-to)2842-2849
Number of pages8
ISSN2161-5063
DOIs
Publication statusPublished - 2021

Keywords

  • biosensor
  • industrial biotechnology
  • metabolite production
  • population heterogeneity
  • production control
  • synthetic circuit balancing

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