TY - JOUR
T1 - Heterologous Production of Fosfomycin and Identification of the Minimal Biosynthetic Gene Cluster
AU - Woodyer, Ryan D.
AU - Shao, Zengyi
AU - Thomas, Paul M.
AU - Kelleher, Neil L.
AU - Blodgett, Joshua A.V.
AU - Metcalf, William W W.
AU - van der Donk, Wilfred A.
AU - Zhao, Huimin
N1 - Funding Information:
We thank Metcalf group member Andrew Eliot for help with Streptomycete microbiology techniques as well as useful discussions on biosynthetic cluster cloning and molecular genetics. We thank Tyler Johannes for repeating the bioassays. We are also grateful to Chris Wright and Laura Guest of the University of Illinois Biotechnology Center for their help with DNA sequencing. This work was supported in part by grants from the National Institutes of Health (GM63003 to W.A.V., GM059334B to W.W.M.), a gift from the Packard Foundation to N.L.K., and a grant from the Office of Naval Research (N00014-02-1-0725 to H.Z.). P.M.T. was supported by a NIH Training Program at the Chemistry/Biology Interface at the University of Illinois (5 T32 GM070421-02).
PY - 2006/11
Y1 - 2006/11
N2 - 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.
AB - 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.
KW - CHEMBIO
KW - MICROBES
UR - http://www.scopus.com/inward/record.url?scp=33750971144&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2006.09.007
DO - 10.1016/j.chembiol.2006.09.007
M3 - Article
C2 - 17113999
AN - SCOPUS:33750971144
SN - 1074-5521
VL - 13
SP - 1171
EP - 1182
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 11
ER -