March 16, 2007 | Science | Health and Medicine
Trojan horse strategy defeats drug-resistant bacteria
Justin Reedy       jreedy@u.washington.edu

A new antimicrobial approach can kill bacteria in laboratory
experiments and eliminate life-threatening infections in mice by
interfering with a key bacterial nutrient, according to research led
by a University of Washington scientist. The joint project, conducted
at the UW, the University of Iowa, and the University of Cincinnati,
will be featured in the April 2 issue of the Journal of Clinical
Investigation.

Bacteria are increasingly resistant to antibiotics, and existing drugs
work poorly against chronic infections like those that occur in
wounds, on medical devices and in the lungs of people with cystic
fibrosis. For these reasons, a great deal of research is focused on
finding new antibiotic compounds.

In this study, researchers took a different approach. Rather than
trying to find agents that best killed bacteria in test tubes, they
sought to intensify the stress imposed on microbes by one of the
body's own defense mechanisms.

"The competition for iron is critical in the struggle between bacteria
and host," explained the study's senior author, Pradeep Singh,
associate professor of medicine and microbiology at the UW. "The body
has potent defense mechanisms to keep iron away from infecting
organisms, and invaders must steal some if they are to survive."

Iron is critical for the growth of bacteria and for their ability to
form biofilms, slime-encased colonies of microbes that cause many
chronic infections. "Because iron is so important in infection, we
thought infecting bacteria might be vulnerable to interventions that
target iron," explained Yukihiro Kaneko, senior fellow in microbiology
at the UW and the study's lead author.

To accomplish this, the researchers used gallium, a metal very similar
to iron. "Gallium acts as a Trojan horse to iron-seeking bacteria,"
said Singh. "Because gallium looks like iron, invading bacteria are
tricked, in a way, into taking it up. Unfortunately for the bacteria,
gallium can't function like iron once it's inside bacterial cells."

The researchers showed that gallium killed microbes, and prevented the
formation of biofilms. Importantly, gallium's action was intensified
in low iron condition, like those that exist in the human body.
Gallium was even effective against strains of Pseudomonas aeruginosa
from cystic fibrosis patients that were resistant to multiple
antibiotics. In mice, gallium treatment blocked both chronic and acute
infections caused by this bacterium.

The idea of using gallium as a substitute for iron was developed by a
group led by Bradley Britigan, a researcher at the University of
Cincinnati and a co-author on this study. The general approach of
targeting stresses already applied by natural defense mechanisms could
be a promising new way to treat infections.

"We badly need new approaches to fight bacteria," said Singh. "The
gallium strategy isn't ready for clinical use yet," he added.
"However, we think this approach is promising, and we can't afford to
leave any stone unturned."

In addition to researchers from the UW and Cincinnati, the study also
included Matthew Thoendel, a medical student at the University of
Iowa. The research was supported by the Cystic Fibrosis Foundation and
the National Institutes of Health.

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