Abstract
ABSTRACTFermentation-based chemical production strategies provide a feasible route for the rapid, safe, and sustainable production of a wide variety of important chemical products, ranging from fuels to pharmaceuticals. These strategies have yet to find wide industrial utilization due to their inability to economically compete with traditional extraction and chemical production methods. Here, we engineer for the first time the complex microbial biosynthesis of an anthocyanin plant natural product, starting from sugar. This was accomplished through the development of a synthetic, 4-strain Escherichia coli polyculture collectively expressing 15 exogenous or modified pathway enzymes from diverse plants and other microbes. This synthetic consortium-based approach enables the functional expression and connection of lengthy pathways while effectively managing the accompanying metabolic burden. The de novo production of specific anthocyanin molecules, such as calistephin, has been an elusive metabolic engineering target for over a decade. The utilization of our polyculture strategy affords milligram-per-liter production titers. This study also lays the groundwork for significant advances in strain and process design toward the development of cost-competitive biochemical production hosts through nontraditional methodologies.
Highlights
Fermentation-based chemical production strategies provide a feasible route for the rapid, safe, and sustainable production of a wide variety of important chemical products, ranging from fuels to pharmaceuticals
These gains were realized through utilization of the key advantages of microbial consortia, including (i) selection of the most efficient organism for the bioconversion, (ii) use of traditional metabolic engineering principles (“push, pull, block”) to optimize each module for its specific cofactor and precursor needs, (iii) taking advantage of consortium modularity such that individual strains can be genetically optimized in monoculture and applied in mixed culture without the need to reperform the genetic optimization, and (iv) capitalizing on the natural transportation of intermediate pathway metabolites in and out of the cells
We showcased, for the first time outside of plants, the production of the anthocyanidin3-O-glucoside callistephin from glucose. This complicated feat was facilitated by the modularity of the polyculture platform, which conserves the genetic optimization of each module and only requires basic fermentation optimization to achieve peak production
Summary
Fermentation-based chemical production strategies provide a feasible route for the rapid, safe, and sustainable production of a wide variety of important chemical products, ranging from fuels to pharmaceuticals. Several excellent examples of employing microbial communities for metabolic engineering have resulted in significant improvements over monoculture efforts [14] These gains were realized through utilization of the key advantages of microbial consortia, including (i) selection of the most efficient organism for the bioconversion (i.e., mixing bacterial and fungal hosts in a single consortium), (ii) use of traditional metabolic engineering principles (“push, pull, block”) to optimize each module for its specific cofactor and precursor needs, (iii) taking advantage of consortium modularity such that individual strains can be genetically optimized in monoculture and applied in mixed culture without the need to reperform the genetic optimization, and (iv) capitalizing on the natural transportation of intermediate pathway metabolites in and out of the cells. Given the benefits of microbial consortia, this presents a unique motivation for researchers to vigorously investigate and engineer both natural and novel transport systems for targeted pathway intermediates
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