Research group gets $7 million to pursue new antibiotic agents
CHAMPAIGN, Ill. —
The National Institutes of Health has awarded $7 million to a team of
researchers from the University of Illinois and the University of Wisconsin
to discover, engineer and produce a promising – yet little explored
– class of antibiotic agents.
The research will look for alternatives to standard antibiotics, which
are losing their effectiveness against common infectious agents. Health
experts worldwide are concerned about the spread of antibiotic-resistant
microbial infections and the shrinking arsenal of compounds that can
effectively treat them.
The five-year effort will explore the medical potential of a class of
compounds called phosphonates. These compounds already have shown promise
in treating infectious diseases such as malaria, and may also be useful
in managing some chronic medical conditions. Phosphonates work by inhibiting
cellular processes that involve naturally occurring phosphorylated compounds.
“There is the potential to discover a phosphonate inhibitor for
every biochemical pathway that involves phosphorylated intermediates,”
said microbiology professor
William W. Metcalf, a principal investigator on the study. “Because
these compounds are widespread in biological processes, the range of
targets is very large."
Metcalf is one of five principal investigators at the U. of I., all
of whom have appointments at the Institute
for Genomic Biology. His collaborators are William H. and Janet
Lycan professor of chemistry
Willem (Wilfred) A. van der Donk, chemical
and biomolecular engineering professor Huimin Zhao, chemistry professor
Neil Kelleher and biochemistry
professor Satish Nair, of the Center
for Biophysics and Computational Biology. Jo Handelsman, of the
University of Wisconsin, also will contribute to the effort.
Metcalf, a microbial geneticist, has long been intrigued by bacterial
phosphate metabolism. He has discovered and biochemically characterized
a number of previously unknown enzymes involved in the microbial metabolism
of phosphate compounds.
About 70 percent
of the antibiotics currently in use come from bacteria. Metcalf’s fascination with the ongoing “biological warfare
between bacteria” led him to explore the antimicrobial potential
of phosphonates. While phosphonates have found uses in medicine –
to treat malaria or hypertension – this area of research is fairly
new, he said.
“No one has even made a dedicated search for phosphonates in nature,”
he said.
Metcalf and his
collaborators have analyzed the biological activity of some known
phosphonates,such as the herbicide phosphinothricin. The van der
Donk and Zhao groups have investigated the clinically used phosphonate,
fosfomycin.
Kelleher, a biological mass spectroscopist, has constructed several
new, high-resolution Fourier Transform mass spectrometers, which will
help the researchers isolate previously unknown microbial products
that contain the phosphonate group.
Nair is an X-ray crystallographer with expertise in elucidating the
three-dimensional structure of protein and DNA complexes.
The research team has four goals: the discovery and genetic characterization
of phosphonate biosynthetic pathways; the biochemical reconstruction
of those pathways that have antibiotic or other therapeutic potential;
the bioengineering of medically useful phosphonates and their biosynthetic
enzymes for economical production; and the use of the latest mass spectrometric
technology to discover and engineer phosphonates and enzymes that contribute
to phosphonate metabolism.
“Our role is the discovery of antibiotics for which there is a
critical need and the development of ways to produce these antibiotics
economically,” Metcalf said.
Editor’s note: To reach William Metcalf, call 217-244-1943; e-mail: metcalf@uiuc.edu.
