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Molecular technique shows promise
in destroying drug resistance in bacteria
photo to enlarge
by Kwame Ross
professor Paul Hergenrother, second from right, and
graduate students, from left, Jason R. Thomas, Johna
C.B. DeNap and Dinty J. Musk have discovered a new
approach to outwit resistance to antibiotics.
Ill. — A new approach to outwit resistance to antibiotics has
been discovered by a team of researchers at the University of Illinois
By inserting a naturally occurring molecule into an antibiotic-resistant
bacterium, the team was able to gradually destroy the machinery responsible
for the resistance.
“Multidrug-resistant bacteria are now ubiquitous in both hospital
settings and the larger community,” wrote Paul J. Hergenrother,
a professor of chemistry,
in a paper that appeared online ahead of publication in the Journal
of the American Chemical Society. “Clearly, new strategies and
targets are needed to combat drug-resistant bacteria.”
Antibiotic resistance makes it difficult to fight infection and increases
the chance of acquiring one while in a hospital. That, in turn, has
led to more deaths from infection, longer hospital stays and a greater
use of more toxic and expensive drugs, according to the National Institutes
Resistance occurs when bacteria develop ways to make themselves impervious,
such as by pumping antibiotics out of the cell, preventing them from
entering the cell or demolishing them. A common way bacteria develop
resistance is by laterally transferring plasmids – pieces of extra-chromosomal
DNA – from one bacterium to another. These plasmids contain genetic
codes for proteins that make bacteria insensitive to antibiotics.
“Our idea was that if you could eliminate plasmids that make the
bacterium resistant, then the bacterium could be sensitive to antibiotics
again,” Hergenrother said.
The researchers’ approach was to use a natural process called
plasmid incompatibility. “If there is one plasmid in a cell and
another one is introduced, then they compete with each other for resources,”
Hergenrother said. “One of them wins and the other is eliminated.”
With the help of chemistry graduate students Johna C.B. DeNap, Jason
R. Thomas and Dinty J. Musk, Hergenrother developed a technique that
mimicked plasmid incompatibility by incubating bacteria containing plasmids
with a specific compound – in this case an aminoglycoside called
apramycin that binds to plasmid-encoded RNA and prevents proper plasmid
Apramycin was chosen after numerous potential aminoglycosides –
a group of antibiotics effective against gram-negative bacteria –
were tested to find those that bind tightly to the target plasmids.
Positively charged apramycin bound to negatively charged plasmid-encoded
RNA, which allowed apramycin to prevent the actions of the protein that
triggers plasmid reproduction. By thwarting that protein, apramycin
blocked plasmid replication.
The apramycin treatment was applied to bacterial cultures that were
grown for 250 generations. By the end of the experiment, the plasmids
no longer were present, making it possible for antibiotics to work.
“This is the first demonstration of a mechanistic-based approach
to systematically eliminate the plasmids,” Hergenrother said.
“Standard antibiotics target the cell wall, but as resistance
to antibiotics emerges, there needs to be other targets. We validated
that plasmids as a new target for antibiotics.”
Further studies are needed to identify whether apramycin is useful against
the plasmids occurring in different strains of antibiotic-resistant
bacteria. It is possible that other compounds may be needed to target
specific plasmids, Hergenrother said. Future studies in his lab will
investigate those questions.
The Office of Naval Research, the National Institutes of Health and
the Research Corporation, a private Arizona-based foundation that supports
basic research in the physical sciences, funded the work.