Apr. 30, 2004 COLUMBUS, Ohio – Scientists have unraveled the behavior of one key component of bacteria, a finding that may lead to better, more effective antibiotics.
The researchers studied a mechanism of action they call the "magic spot" – an important regulator of gene expression. They describe their results in the current issue of the journal Cell.
Researchers know that the magic spot – a molecule known as guanosine-tetraphosphate or ppGpp – is involved in how bacteria respond to amino acid starvation. More recently, researchers have discovered that ppGpp is an important part of pathogens that cause illnesses such as cholera and Legionnaires' disease.
A cell makes ppGpp when amino acid levels are low.
"Microbiologists have wondered for a half-century how this small molecule with a relatively simple structure could have such a profound effect on regulating a cell's survival," said Irina Artsimovitch, a study co-author and an assistant professor of microbiology at Ohio State University. She collaborated on this work with study lead author Dmitry Vassylyev, of the RIKEN Institute in Japan.
ppGpp controls what researchers call the "stringent response" – a condition of nutritional starvation. When amino acid pools in a cell are exhausted, ppGpp accumulates and shuts down the synthesis of new proteins. The cell goes dormant until amino acid levels return to normal.
By learning the structure of ppGpp and how it interacts with the enzyme RNA polymerase – the main enzyme that controls gene expression in a cell – the researchers were able to describe in detail the "magic" behind the magic spot, Artsimovitch said.
"This study sheds a good deal of light on the inner workings of the molecular machinery that carries out gene expression in bacteria," she said. "Knowing this can serve as a basis for a new type of antibiotics.
In related work reported in a recent issue of the Journal of Bacteriology, Artsimovitch led a team of researchers in learning how a protein that is specific to illness-causing bacteria might provide another potential path to developing antibiotics against bacteria that cause cholera, pneumonia and food poisoning.
This protein, called RfaH, regulates virulence – a bacterium's ability to cause disease – in pathogens such as Escherichia coli and Salmonella enterica, bacteria that cause food poisoning in humans.
Artsimovitch and her colleagues identified previously overlooked RfaH genes in other bacterial pathogens, such as those that cause cholera and bubonic plague.
"Not only do RfaH proteins from different bacteria look similar, they act similar, too," she said.
Without RfaH, enterobacteria can't cause disease, Artsimovitch said. It's plausible that drug developers could design an antibiotic that knocks out RfaH, effectively shutting down a bacterium's virulence.
"We're trying to give the scientists who work on these pathogens detailed models of RfaH and ppGpp behavior," Artsimovitch said. "That may lead to better-targeted antibiotics that can really be effective against these diseases."
Support for these studies came from the American Heart Association and the National Institutes of Health.
Artsimovitch and Vassylyev conducted the work reported in Cell with researchers from the RIKEN Harima Institute in Hyogo, Japan; the RIKEN Genomic Sciences Center in Yokohama, Japan; the National Food Research Institute in Ibaraki, Japan; and the University of Tokyo. Artsimovitch conducted the work reported in the Journal of Bacteriology with Ohio State researchers Heather Carter and Vladimir Svetlov.
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