Format

Send to

Choose Destination
Nat Chem Biol. 2018 Aug;14(8):794-800. doi: 10.1038/s41589-018-0084-6. Epub 2018 Jun 25.

Metabolic engineering of a carbapenem antibiotic synthesis pathway in Escherichia coli.

Author information

1
Department of Bionanoscience, Kavli Institute of Nanoscience, Delft University of Technology, Delft, the Netherlands.
2
Centre for Research and Interdisciplinarity (CRI), Paris Descartes University, Paris, France.
3
Department of Biotechnology, Delft University of Technology, Delft, the Netherlands.
4
Department of Bionanoscience, Kavli Institute of Nanoscience, Delft University of Technology, Delft, the Netherlands. G.E.Bokinsky@tudelft.nl.

Abstract

Carbapenems, a family of β-lactam antibiotics, are among the most powerful bactericidal compounds in clinical use. However, as rational engineering of native carbapenem-producing microbes is not currently possible, the present carbapenem supply relies upon total chemical synthesis of artificial carbapenem derivatives. To enable access to the full diversity of natural carbapenems, we have engineered production of a simple carbapenem antibiotic within Escherichia coli. By increasing concentrations of precursor metabolites and identifying a reducing cofactor of a bottleneck enzyme, we improved productivity by 60-fold over the minimal pathway and surpassed reported titers obtained from carbapenem-producing Streptomyces species. We stabilized E. coli metabolism against antibacterial effects of the carbapenem product by artificially inhibiting membrane synthesis, which further increased antibiotic productivity. As all known naturally occurring carbapenems are derived from a common intermediate, our engineered strain provides a platform for biosynthesis of tailored carbapenem derivatives in a genetically tractable and fast-growing species.

PMID:
29942079
DOI:
10.1038/s41589-018-0084-6
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center