Biosynthesis of β-lactam nuclei in yeast

We have engineered brewer's yeast as a general platform for de novo synthesis of diverse 8-lactam nuclei starting from simple sugars, thereby enabling ready access to a number of structurally different antibiotics of significant pharmaceutical importance. The biosynthesis of beta-lactam nuclei has received much attention in recent years, while rational engineering of non-native antibiotics-producing microbes to produce beta-lactam nuclei remains challenging. Benefited by the integration of heterologous biosynthetic pathways and rationally designed enzymes that catalyze hydrolysis and ring expansion reactions, we succeeded in constructing synthetic yeast cell factories which produce antibiotic cephalosporin C (CPC, 170.1 +/- 4.9 mu g/g DCW) and the downstream 8-lactam nuclei, including 6-amino penicillanic acid (6-APA, 5.3 +/- 0.2 mg/g DCW), 7-amino cephalosporanic acid (7-ACA, 6.2 +/- 1.1 mu g/g DCW) as well as 7-amino desacetoxy cephalosporanic acid (7-ADCA, 1.7 +/- 0.1 mg/g DCW). This work established a Saccharomyces cerevisiae platform capable of synthesizing multiple beta-lactam nuclei by combining natural and artificial enzymes, which serves as a metabolic tool to produce valuable beta-lactam intermediates and new antibiotics.

Automated summary

This study established a platform using engineered brewer's yeast for the synthesis of various β-lactam nuclei, allowing access to structurally different antibiotics. By integrating heterologous biosynthetic pathways and designed enzymes, the researchers successfully produced valuable antibiotic intermediates, demonstrating the significance of this work for antibiotic production.