New antibiotic toxicity test
Yeast gene screen gives clues to
human adverse drug reactions.
4 February 2003
KENDALL POWELL
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| Up to 10% of people develop
a reaction to antibiotics. |
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Researchers are using yeast to home in on the genes behind
people's adverse reactions to antibiotics. The method could also
help to screen new antibiotics for toxicity earlier in drug
development, before they reach animal or human trials.
Some 5-10% of us develop symptoms ranging from harmless
rashes to serious allergies or organ damage when we are treated
with antibiotics.
"If we can identify genetic differences associated with
antibiotic sensitivities," explains microbiologist Simon Avery
of the University of Nottingham, UK, "it should be possible in
the future to take snapshots of a person's genes and tailor
their prescription."
Screening the human genome for such defects would be almost
impossible at the moment. So Avery and colleague Alexandra
Blackburn looked through the much smaller genome of the yeast
Saccharomyces cerevisiae1. They
used a library of strains, each missing a different one of every
single gene in the yeast's genome.
"More than 40% of human genes linked to conditions or
diseases have yeast counterparts," explains Avery. Yeast cells
operate in a similar way to human ones and are easy to grow and
handle in the lab.
The duo treated each strain with several antibiotics to find
which gene deletions make the cells susceptible to which
antibiotics. Only bacteria should be sensitive to these
antibiotics, so an ailing yeast could be mimicking an adverse
human cell response.
The scientists found 17 genes that make yeast slow or stop
growing when exposed to gentamicin. This cheap and powerful
antibiotic is used to treat skin, eye, and ear infections and
bacterial meningitis. In 5- 10% of patients it can damage the
kidneys and inner ear.
"Understanding how gentamicin does its damage would be very
important in figuring out how to avoid this toxicity," says
Timothy Hain, a neurologist at Northwestern University in
Evanston, Illinois.
The screen also identified four genes that make yeast
sensitive to tetracycline and oxytetracycline, which are
antibiotics used to treat Lyme disease, pneumonia, acne, bladder
infections and ulcers. Figuring out how to prevent antibiotic
toxicity in patients based on the molecules identified here will
be a much more daunting task, however.
The sift did not reveal any deletions that make cells
susceptible to amoxicillin, penicillin, rifampin or vancomycin,
which are used to treat bacterial infections of the airways,
stomach and skin. This could be due to differences in the way in
which human and yeast cells take up antibiotics, says Avery. He
admits that the screen probably missed some gene functions that
are specific to humans. |
