Bacterial Transcription Factor Might Be Drug Target

Researchers have determined the crystal structure of the Escherichia coli DksA protein and have assigned it a crucial role in regulating gene expression in this and other bacteria.

Investigators at Ohio State University (Columbus, USA) in collaboration with researchers from several Japanese institutions reported in the August 6, 2004, issue of Cell that the 2.0 angstrom resolution structure of DksA revealed a globular domain and a coil with two highly conserved aspartate residues at its tip that was reminiscent of the transcript cleavage factor GreA.

DksA is a component of the alarmone ppGpp that had been shown previously to regulate RNA transcription in bacteria. ppGpp binds near the catalytic site of RNA polymerase (RNAP) and modulates its activity. Alarmones are an unusual class of small dinucleotide signal molecules produced by bacteria under stress that induce an alteration of metabolism. Many metabolic responses may be altered by a single alarmone.

The investigators suggested that DksA might be a good target for antibacterial drugs. "Conventional antibiotics aimed at killing bacteria also put immense pressure on bacteria to survive, and to ultimately develop resistance to these drugs,” said contributing author Dr. Irina Artsimovitch, assistant professor of microbiology at Ohio State University. "Forcing harmful bacteria into a stationary state by controlling ppGpp levels may be the way to circumvent the rise in antibiotic resistance. ppGpp and DksA are found in all bacteria, including harmful ones. Using ppGpp-based compounds to shut down gene expression in harmful bacteria could help curb the spread of infections.”



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