Scientists determine structure of enzyme that disrupts bacterial virulence

First step toward developing enzymes to treat diseases such as cystic fibrosis, reduce bacterial biological warfare threats

A team of biomedical researchers from The University of Texas at Austin and Brandeis University has determined the first 3-dimensional structure of an enzyme that may be critical in preventing certain bacterial infections in plants, animals and humans.

The enzyme had been shown in previous studies to significantly decrease soft rot in potato plants. The UT and Brandeis team purified the enzyme and identified its structure using X-ray crystallography, an essential step toward developing drugs that may reduce the pathogenicity of bacteria involved in some biological warfare threats and diseases such as cystic fibrosis. The findings were recently published in the Proceedings of the National Academy of Sciences.

Walter Fast, assistant professor of medicinal chemistry at UT Austin's College of Pharmacy, led the UT aspect of the study while Dagmar Ringe directed investigations at the Rosenstiel Basic Medical Sciences Research Center at Brandeis.

"This study represents a significant advance in understanding how this enzyme can prevent certain bacteria from becoming virulent," explained Ringe of the Rosenstiel Basic Medical Sciences Research Center at Brandeis. "One of the promising aspects of potential therapies based on this enzyme is that it targets a different pathway than current antibiotics."

The enzyme works by disrupting the ability of certain bacteria to sense their own population growth ­ the key to triggering genes that can increase virulence. In order to sense the size of their own populations, certain bacteria produce small molecules called N-acyl homoserine lactones. The concentrations of these lactones increase along with the growth of the bacterial population. After reaching a threshold concentration, the lactones can "turn on" a variety of genes, often increasing the virulence of the accumulating bacteria.

This population-sensing results in a type of bacterial "group think" because certain genes are not turned on until a minimum number of bacteria are present. Hence, this phenomenon is called quorum-sensing.

"Being able to disrupt quorum-sensing in these organisms could potentially augment our current treatments, and knowing the structure of this quorum-quenching enzyme will greatly help in developing more effective enzymes for this type of application," explained UT's Walter Fast.

In addition to treating plant pathogens, the hope is that these quorum-quenching enzymes may eventually be developed for use in treating human and animal pathogens that also rely on quorum-sensing for their virulence.

For example, bacterial pathogens such as Burkholderia mallei, which is responsible for the biowarfare threat glanders, and Pseudomonas aeruginosa, which often forms opportunistic infections on the lung surfaces of patients with cystic fibrosis, rely on their quorum-sensing systems to increase their pathogenicity and resistance to antibiotics.