1887

Abstract

Genetic engineering has been applied to reprogramme non-ribosomal peptide synthetases (NRPSs) to produce novel antibiotics, but little is known about what determines the efficiency of production. We explored module exchanges at nucleotide sequences encoding interpeptide linkers in , a gene encoding a di-modular NRPS subunit that incorporates 3-methylglutamic acid (3mGlu) and kynurenine (Kyn) into daptomycin. Mutations causing amino acid substitutions, deletions or insertions in the inter-module linker had no negative effects on lipopeptide yields. Hybrid DptD subunits were generated by fusing the 3mGlu module to terminal modules from calcium-dependent antibiotic (CDA) or A54145 NRPSs, and recombinants produced daptomycin analogues with Trp or Ile at high efficiencies. A recombinant expressing DptD with a hybrid Kyn module containing a di-domain from a -Asn module caused the production of a new daptomycin analogue containing Asn.

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2008-09-01
2020-03-29
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