| CHAMPAIGN,
Ill. — A new approach to outwit resistance to antibiotics
has been discovered by a team of researchers at the
University of Illinois at Urbana-Champaign.
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
of Health.
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 reproduction.
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.
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