Heterologous Production of Fosfomycin and Identification of the Minimal Biosynthetic Gene Cluster

Ryan D. Woodyer, Zengyi Shao, Paul M. Thomas, Neil L. Kelleher, Joshua A V Blodgett, William W Metcalf, Wilfred A. van der Donk*, Huimin Zhao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Fosfomycin is a clinically utilized, highly effective antibiotic, which is active against methicillin- and vancomycin-resistant pathogens. Here we report the cloning and characterization of a complete fosfomycin biosynthetic cluster from Streptomyces fradiae and heterologous production of fosfomycin in S. lividans. Sequence analysis coupled with gene deletion and disruption revealed that the minimal cluster consists of fom1-4, fomA-D. A LuxR-type activator that was apparently required for heterologous fosfomycin production was also discovered ∼13 kb away from the cluster and was named fomR. The genes fomE and fomF, previously thought to be involved in fosfomycin biosynthesis, were shown not to be essential by gene disruption. This work provides new insights into fosfomycin biosynthesis and opens the door for fosfomycin overproduction and creation of new analogs via biomolecular pathway engineering.

Original languageEnglish (US)
Pages (from-to)1171-1182
Number of pages12
JournalChemistry and Biology
Volume13
Issue number11
DOIs
StatePublished - Nov 2006

Keywords

  • CHEMBIO
  • MICROBES

ASJC Scopus subject areas

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

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