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Date: May 19, 2000

Penicillin Research May Lead To New Drug Treatments

Twenty years ago Dr. Edward Ishiguro came up with a solution to a problem that had stumped scientists since the discovery of penicillin in 1928. His discovery and subsequent research have opened up new possibilities in antibiotic drug treatment.

The problem that Ishiguro solved was penicillin tolerance --penicillin's inability to kill bacteria when they are not growing. Growing bacterial cells are susceptible to penicillin, but non-growing cells are tolerant.

Though scientists had long been aware of this phenomenon, they had not been able to overcome it. Not, that is, until Ishiguro, chair of UVic's biochemistry and microbiology department, realized tolerance was directly related to cell starvation.

Penicillin and similar antibiotics work by targeting the cell wall of bacteria. Starving or non-growing cells produce a chemical called guanosine tetraphosphate which acts a signal for the cell to shut down its energy-consuming operations and go into stasis--a state of inactivity.

Using E. coli bacteria as a model, Ishiguro developed a test that showed that guanosine tetraphosphate triggers a shutdown response in penicillin's target --a protein responsible for the construction and expansion of the cell wall --making it impossible for penicillin to interact with it and destroy the bacteria.

Subsequently, Ishiguro found that he could inhibit the production of guanosine tetraphosphate in starving cells.

"Guanosine tetraphosphate --the starvation signal chemical --is made by a protein associated with the cell ribosome, the structure on which cell proteins are produced," says Ishiguro. "We found that drugs that target ribosomes, by pure chance, inhibit the formation of the chemical." This fools the bacteria into behaving like normal growing cells and keeps them susceptible to penicillin.

Ishiguro says that while a combination of these ribosome-targetting drugs and penicillin can kill non-growing bacteria, such combination therapy isn't perfect.

"They don't target the specific action of the protein, and, moreover, many bacteria have already become resistant to these drugs."

Resistance, which is not the same as tolerance, results when bacteria adapt to an antibiotic that has been in use for a long time.

For the past two years, Ishiguro's team has been studying the protein that releases guanosine tetraphosphate, an effort that could lead to drugs that block its specific action. This protein may represent an important new drug target.

"The discovery of new drug targets is so important today due to the growing problem of bacterial drug resistance," he says.

Research into guanosine tetraphosphate is also crucial because scientists have found the chemical allows bacteria to resist the body's defence mechanisms as well as drug treatment. Starving cells, for example, can tolerate acid attacks in the stomach.

"The human body has perfectly good defense mechanisms," says Ishiguro. "If we can short-circuit the production of this chemical we can make bacteria more sensitive to both drugs and the body's own defences."
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Media contacts:
Dr. Ed Ishiguro (biochemistry & microbiology) at (250) 721-7071.

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