Researchers at the University of Illinois at Chicago, in collaboration with research teams from Pharmacia & Upjohn and Pfizer, have discovered precisely how the antibiotic linezolid inhibits bacterial growth.
Scientists have known that the drug linezolid -- the first new antibiotic to enter the marketplace in 30 years -- works by binding to ribosomes, the protein production factory of the cell. But exactly where the binding occurred and how the drug worked was not known. Until now.
"Linezolid targets ribosomes, inhibits protein synthesis, and kills bacteria," said Alexander Mankin, professor and associate director of UIC's Center for Pharmaceutical Biotechnology and lead investigator of the study. "If we know exactly where the drug binds, we can make it better and learn how to use it more effectively."
Linezolid is a synthetic antibiotic used for the treatment of infections caused by pathogens such as staph and strep, including multi-drug-resistant bacteria. Skin infections, pneumonia, and other diseases can be treated with linezolid. It is marketed in the United States as Zyvox.
Mankin and his colleagues managed not only to crosslink the drug to its target in the living cell, but to precisely characterize the mode of binding of the drug to the ribosome. "It was a combined effort of excellent chemists, structural biologists and biochemists," Mankin said.
"We now understand much better how the drug works, how it can be improved, and how bacteria can become resistant to linezolid."
A second part of the study involved learning why, in rare cases, the drug can have side effects causing a decrease in the production of blood cells. By crosslinking linezolid to its target in human cells, the researchers showed that the drug may be toxic to mitochondria -- the power generators of the cell -- which contain ribosomes that resemble the ribosomes of bacteria. "This is the first time such detailed information about the linezolid target in the living cell has been obtained," Mankin said.
The findings are published in the May 11 issue of the journal Molecular Cell.
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