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Cloning techniques produce FDA-approved antibiotic
Kristen
Aramthanapon, News Bureau
217-244-8780, aramthan@uiuc.edu
Released
11/27/06
CHAMPAIGN, Ill. —
The successful synthesis of an antibiotic in a non-native host has
provided a team of researchers at the University of Illinois at
Urbana-Champaign with the potential for developing new treatments
for bacterial infections.
The rapid rise of antibiotic resistance poses a serious threat to human
health, and demands new treatments effective against resistant pathogens.
Fosfomycin is a natural antibiotic approved by the Food and Drug Administration
for the treatment of various bacterial infections, and has proven effective
for the treatment of infections that have become resistant to the antibiotics
penicillin and vancomycin.
Fosfomycin is a member of a class of compounds called phosphonic acids
because they contain a carbon-phosphorous bond. Fosfomycin functions
by inactivating an essential enzyme involved in the formation of the
bacterial cell wall.
“Phosphonic acids are underexploited bioactive compounds with
great potential for treating human disease,” said Huimin Zhao,
a U. of I. professor of chemical
and biomolecular engineering. “We hope to understand the complete
pathway for how fosfomycin is made.”
In a paper to appear in the Nov. 27 journal Chemistry and Biology, Zhao
and U. of I. chemistry professor
Wilfred A. van der Donk report the first successful synthesis of fosfomycin
in a non-native host.
Fosfomycin is produced by various species of bacteria, but generally
in low yields. Using a cloning method developed by Illinois microbiologist
William W. Metcalf, the researchers were able to clone the essential
genes for fosfomycin synthesis and then produce it in a non-native host,
potentially in much larger quantities.
After isolating the genetic information from fosfomycin’s native
host, Streptomyces fradiae, certain genes were inactivated, and the
ability of a non-native host Streptomyces lividians to produce fosfomycin
was assessed.
With the help of graduate students Ryan Woodyer and Zengyi Shao, Zhao
and van der Donk were able to determine not only the minimal set of
genes required for fosfomycin biosynthesis, but also the function of
some of these genes.
“Our goal now is to produce fosfomycin in Escherichia coli so
that we can use various protein and metabolic engineering tools to manipulate
the fosfomycin biosynthetic pathway,” said Zhao, who also is an
affiliate of the university’s Institute
for Genomic Biology. “Eventually, we should be able to produce
fosfomycin in a cost-effective manner and create more potent derivatives
of it.”
Previously, four essential genes and a portion of fosfomycin’s
biosynthetic pathway had been proposed, but researchers were unable
to produce fosfomycin in a non-native host. Zhao’s findings indicate
that the presence of additional genes that result in a revised mechanism
is crucial for successful fosfomycin biosynthesis.
The other co-authors of the paper are chemistry professor Neil Kelleher, microbiology professor
William Metcalf and graduate students Paul Thomas and Joshua Blodgett.
The work was funded in part by the National Institutes of Health, the
Office of Naval Research, and the Packard Foundation.
Editor’s note: To reach Huimin Zhao, call 217-333-2631; e-mail: zhao5@uiuc.edu.
