TY - JOUR
T1 - Metabolic engineering of a carbapenem antibiotic synthesis pathway in Escherichia coli
AU - Shomar, Helena
AU - Gontier, Sophie
AU - van Den Broek, Niels J.F.
AU - Tejeda Mora, Héctor
AU - Noga, Marek J.
AU - Hagedoorn, Peter Leon
AU - Bokinsky, Gregory
PY - 2018/6/25
Y1 - 2018/6/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85048962896&partnerID=8YFLogxK
U2 - 10.1038/s41589-018-0084-6
DO - 10.1038/s41589-018-0084-6
M3 - Article
AN - SCOPUS:85048962896
SN - 1552-4450
SP - 1
EP - 7
JO - Nature Chemical Biology
JF - Nature Chemical Biology
ER -