Research Group Gets $ 7 Million To Pursue New 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.