Directed evolution of the nonribosomal peptide synthetase AdmK generates new andrimid derivatives in vivo

Bradley S. Evans, Yunqiu Chen, William W. Metcalf, Huimin Zhao, Neil L. Kelleher

Research output: Contribution to journalArticle

Abstract

Many lead compounds in the search for new drugs derive from peptides and polyketides whose similar biosynthetic enzymes have been difficult to engineer for production of new derivatives. Problems with generating multiple analogs in a single experiment along with lack of high-throughput methods for structure-based screening have slowed progress in this area. Here, we use directed evolution and a multiplexed assay to screen a library of >14,000 members to generate three derivatives of the antibacterial compound, andrimid. Another limiting factor in reengineering these mega-enzymes of secondary metabolism has been that commonly used hosts such as Escherichia coli often give lower product titers, so our reengineering was performed in the native producer, Pantoea agglomerans. This integrated in vivo approach can be extended to larger enzymes to create analogs of natural products for bioactivity testing.

Original languageEnglish (US)
Pages (from-to)601-607
Number of pages7
JournalChemistry and Biology
Volume18
Issue number5
DOIs
StatePublished - May 27 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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