A team of biomedical researchers from Brandeis University and theUniversity of Texas at Austin has determined the first 3-dimensionalstructure of an enzyme that may be pivotal in preventing certainbacterial infections in plants, animals and humans, according to astudy published in the Proceedings of the National Academy of Sciences.
The enzyme had already been shown in previous studies tosignificantly decrease soft rot in potato plants. The Brandeis andUniversity of Texas team purified the enzyme and identified itsstructure using X-ray crystallography, an essential step towarddeveloping drugs that may reduce the pathogenicity of bacteria involvedin biowarfare threats such as glanders and diseases such as cysticfibrosis.
"This study represents a significant advance in understandinghow this enzyme can prevent certain bacteria from becoming virulent,"explained Dagmar Ringe of the Rosenstiel Basic Medical SciencesResearch Center at Brandeis University. "One of the promising aspectsof potential therapies based on this enzyme is that it targets adifferent pathway than current antibiotics."
The enzyme works by disrupting the ability of certain bacteriato sense their own population growth -- the key to triggering genesthat can increase virulence. In order to sense the size of their ownpopulations, certain bacteria produce small molecules called N-acylhomoserine lactones. The concentrations of these lactones increasealong with the growth of the bacterial population. After reaching athreshold 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 "groupthink" because certain genes are not turned on until a minimum numberof bacteria are present. Hence, this phenomenon is calledquorum-sensing.
"Being able to disrupt quorum-sensing in these organisms couldpotentially augment our current treatments, and knowing the structureof this quorum-quenching enzyme will greatly help in developing moreeffective enzymes for this type of application," explained Walter Fast,assistant professor in the College of Pharmacy at the University ofTexas at Austin.
In addition to treating plant pathogens, the hope is thatthese quorum-quenching enzymes may eventually be developed for use intreating human and animal pathogens that also rely on quorum-sensingfor their virulence.
For example, bacterial pathogens such as Burkholderia mallei,which is responsible for the biowarfare threat glanders, andPseudomonas aeruginosa, which often forms opportunistic infections onthe lung surfaces of patients with cystic fibrosis, rely on theirquorum-sensing systems to increase their pathogenicity and resistanceto antibiotics.
These studies were supported by the National Institutes of Health and the Robert A. Welch Foundation.
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