Polymer-Coated Yeast Cells for Enhanced Biosynthesis of Medicine

Metabolic engineering has made significant progress in producing complex and valuable medicinal products in microorganisms by reconstructing heterologous biosynthetic pathways. Such synthetic pathways often comprise a dozen or more sequential reactions. While the metabolic flux of the reaction intermediates could be optimized for improved productivity and/or efficiency, which holds enormous potential, there have been a limited number of reports on such efforts. That is partially due to a dearth of information on the trans-membrane transport mechanisms of the reaction intermediates. This talk will highlight the recent progress in the development of a new paradigm for the facile optimizing metabolic flux, thereby advancing the biosynthesis of medicines while reducing the optimizing cost. The paradigm is termed MetaLock, which involves creating a conformal ultrathin coating at the single-cell level to achieve perm-selectivity of nutrients and metabolites. We demonstrate that the coating does not inhibit the permeability of nutrients such as sugars and amino acids but creates a diffusion barrier for reaction intermediates to achieve high reaction rates and boost productivity. Through rational material design characterization and computational modeling, we systematically verify the effectiveness of this concept in regulating metabolic fluxes, first in a 6-step reconstructed reaction and then in an 11-step one, respectively. As such, MetaLock is a generalizable strategy that is applicable to improving the productivity of a variety of synthetic pathways. We seek to underscore the importance of understanding detailed microbe-material interactions and to provide an outlook on leveraging MetaLock to accelerate the development of engineered living materials.