Gallium May Have Antibiotic-Like Properties

By Michael Smith, Senior Staff Writer, MedPage Today
Published: March 16, 2007
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University
of Pennsylvania School of Medicine.

SEATTLE, March 16 -- The metal gallium -- approved as a drug by the
FDA to treat symptomatic cancer-related hypercalcemia -- may also be
useful as an anti-microbial, according to researchers here. Action
Points
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Note that this study suggests -- on the basis of lab experiments and
studies in animals -- that the metal gallium might be an effective
antibiotic agent.

Note that the study is preliminary and more research and ultimately
human studies are needed.
The metal appears to act as a "Trojan horse" to bacteria, taking the
place of iron that the microbes need to grow and replicate, said
Pradeep K. Singh, M.D., of the University of Washington.

In mice, doses of the metal administered nasally were able to prevent
death from a lethal dose of Pseudomonas aeruginosa, the researchers
reported online in the Journal of Clinical Investigation, in advance
of the April print issue.

When the animals' lungs were pre-treated with iron, however, the life-
saving effect of the gallium was not seen, the researchers said.

The work is based on the observation that many bacteria require iron
to grow and replicate and that many biological defense systems operate
on the principle of denying iron to infective agents.

Gallium, a transition metal that is chemically similar to iron, has
been shown to disrupt biological mechanisms that are dependent on
iron, Dr. Singh and colleagues noted.

Their animal studies confirm a range of other in vitro experiments, in
which the metal was shown to have several activities that might make
it useful as an antibiotic, Dr. Singh and colleagues said.

Specifically:

In culture, gallium inhibited the growth of P. aeruginosa, including
multidrug resistant strains isolated from people with cystic
fibrosis.
The metal prevented P. aeruginosa from forming biofilms involved in
chronic bacterial infections.
The metal killed both free-living bacteria and bacteria in biofilms.
To test the effect of the metal in vivo, Dr. Singh and colleagues
inoculated mice with P. aeruginosa strain PA103, at a dose that has
been shown to cause death rapidly.

Three hours later, the mice were made to inhale a 50-microliter drop
of either a gallium compound or a gallium-free vehicle.

Three days after the bacterial infection, all of the control mice had
died, but more than 80% of the gallium-treated mice were still living,
a difference that was significant at P<0.005.

When the mice were treated with an iron compound before the gallium,
they died with a similar pattern as the control mice in the first
experiment, indicating that the extra available iron defeated the
gallium "Trojan horse," the researchers said.

The metal also inhibited the formation of biofilms in a model in which
a small plastic tube is inserted in either main bronchus of mice,
planktonic P. aeruginosa is infused, and a biofilm forms on the tube.

Gallium or a gallium-free vehicle was administered nasally three times
a day for three days, and then the lung tissue was tested for colony-
forming units of P. aeruginosa.

The researchers found that on average, animals treated with gallium
had about 100 colony forming units per lung, compared with about
100,000 for the untreated animals. The difference was significant at
P<0.005.

The study is limited, Dr. Singh and colleagues said, because the
animal models are not ideal, they were unable to rule out an anti-
inflammatory activity that might account for some of the effect of
gallium, and the studies did not give information on the value of the
metal in combating established biofilms.

"Further work and, ultimately, human studies will be needed to
determine whether (gallium) is an effective antimicrobial treatment,"
they concluded.

The research was supported by the Cystic Fibrosis Foundation and the
National Institutes of Health. The authors declared they had no
conflicts of interest.

Additional source: The Journal of Clinical Investigation
Source reference:
Kaneko Y et al. "The transition metal gallium disrupts Pseudomonas
aeruginosa iron metabolism and has antimicrobial and antibiofilm
activity." J Clin Invest 2007; doi:10.1172/JCI30783.

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