As a first step in reaching this goal of developing new drugs, Brookhaven biologist Maria Bewley will use the National Synchrotron Light Source (NSLS) at Brookhaven to determine the structures of three proteins that are found in the metabolic pathways, or sequence of reactions catalyzed by enzymes, that enable lysine to be synthesized by microbes. Lysine is one of eight essential amino acids that humans must consume because they cannot synthesize it.
Fungi and bacteria have pathways that can synthesize lysine. The enzymes in these pathways are ideal targets for developing anti-microbial drugs, since they are absent in humans.
"We can kill fungi and bacteria if we can develop a drug that can block the enzymes in their pathways before they synthesize lysine," Bewley explained. "Since these drugs would attack enzymes that don't exist in humans, it is unlikely that they would have negative effects in the human body."
Designing such drugs, however, is hampered by the lack of structural information about the three enzymes in the lysine pathways. To obtain structural information on them, Bewley will clone and express each of the enzymes using a patented gene expression system, known as T-7, invented by Brookhaven biologists. Then she will purify each enzyme, crystallize it, and expose it to x-rays at the NSLS. A detector records a pattern from the resulting scattered x-ray beam, which allows Bewley to determine the enzyme's structure.
During the first year of the CRADA, Battelle will identify business opportunities to market compounds that inhibit lysine enzymes. Battelle's Robert Miller explained, "The development of antibiotic resistance is a worldwide medical threat. The goal is to use our business strategy and technology innovation competencies to identify the path forward for delivery of anti-microbial compounds and technologies. Ultimately, the success of this program is based on the enzyme structural information collected by Dr. Bewley."
As part of this effort, Battelle plans to set up alliances with academic or industrial partners to begin to design candidate inhibitors of lysine enzymes. The goal is to use the structural information and the business plan to generate funding for the design, preparation, and testing of candidate inhibitors, which might lead to the commercialization of novel anti-microbial drugs.
Battelle is funding this CRADA.
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The U.S. Department of Energy's Brookhaven National Laboratory (http://www.bnl.gov) conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies. Brookhaven also builds and operates major facilities available to university, industrial, and government scientists. The Laboratory is managed by Brookhaven Science Associates, a limited liability company founded by Stony Brook University and Battelle, a nonprofit applied science and technology organization.