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Compounds Block Spread of Antibiotic Resistance
The success of antibiotics is among modern medicine's great achievements.
But microbes have been evolving resistance. Many diseases, including
tuberculosis, gonorrhea and childhood ear infections, are now becoming
more difficult to treat. Researchers have discovered 2 medications
already approved for other uses that can block the transfer of
drug resistance genes between bacteria and even kill bacteria that
harbor resistance genes. This novel type of antibiotic could potentially
be used against multidrug resistant bacteria.
The heavy use of antibiotics allows only those bacteria with the
greatest antibiotic resistance to survive and thrive, thus ensuring
that future generations of bacteria will have greater drug resistance.
Different strains of bacteria can spread drug resistance genes
through a process called conjugation. More than 50 years of widespread
antibiotic use have thus encouraged the spread of bacteria with
resistance to multiple antibiotics.
A team of researchers at the University of North Carolina, Chapel
Hill led by Dr. Matthew R. Redinbo set out to see if they could
find compounds that inhibit conjugation. Conjugation involves bacteria
forming a junction between them and transferring circular pieces
of DNA called plasmids. The study, which was funded by NIH's National
Cancer Institute (NCI) and National Institute of General Medical
Sciences (NIGMS), was published in the July 13, 2007, online edition
of Proceedings of the National Academy of Sciences.
The researchers focused on a DNA relaxase, a type of enzyme involved
in conjugation, from E. coli. DNA relaxase initiates DNA
transfer by nicking one of the plasmid's DNA strands. After analyzing
the structure at the enzyme's active site, the researchers hypothesized
that chemicals called bisphosphonates might inhibit relaxase activity
and therefore block DNA transfer. They tested several bisphosphonates
and found that many inhibited DNA relaxase, including 4 that are
already clinically approved by the U.S. Food and Drug Administration
(FDA) to treat bone loss.
The researchers next tested whether the compounds could prevent
living bacterial cells from transferring the plasmids. Two of the
clinically approved bisphosphonates, etidronate (Didronel) and
clodronate (Bonefos), were both effective not only at preventing
DNA transfer but also at killing the cells that harbored the plasmids.
This study shows that bisphosphonates are a potential new class
of antibiotics that can prevent the transfer of plasmids, and therefore
drug resistance genes, between bacteria. Further research will
show whether these compounds are effective in living systems.
—by Harrison Wein, Ph.D.
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