"We shouldn't limit ourselves to just single
drugs or two-drug combinations in our medical toolbox," said Pamela Yeh
(left), with Elif Tekin.
Credit: Reed Hutchinson/UCLA
Scientists have traditionally believed that
combining more than two drugs to fight harmful bacteria would yield
diminishing returns. The prevailing theory is that that the incremental
benefits of combining three or more drugs would be too small to matter,
or that the interactions among the drugs would cause their benefits to
cancel one another out.
Now, a team of UCLA biologists has discovered thousands of four- and
five-drug combinations of antibiotics that are more effective at killing
harmful bacteria than the prevailing views suggested. Their findings,
reported today in the journal npj Systems Biology and Applications,
could be a major step toward protecting public health at a time when
pathogens and common infections are increasingly becoming resistant to
antibiotics.
"There is a tradition of using just one drug, maybe two," said Pamela
Yeh, one of the study's senior authors and a UCLA assistant professor
of ecology and evolutionary biology. "We're offering an alternative that
looks very promising. We shouldn't limit ourselves to just single drugs
or two-drug combinations in our medical toolbox. We expect several of
these combinations, or more, will work much better than existing
antibiotics."
Working with eight antibiotics, the researchers analyzed how every
possible four- and five-drug combination, including many with varying
dosages -- a total of 18,278 combinations in all -- worked against E. coli.
They expected that some of the combinations would be very effective at
killing the bacteria, but they were startled by how many potent
combinations they discovered.
For every combination they tested, the researchers first predicted
how effective they thought it would be in stopping the growth of E. coli.
Among the four-drug combinations, there were 1,676 groupings that
performed better than they expected. Among the five-drug combinations,
6,443 groupings were more effective than expected.
"I was blown away by how many effective combinations there are as we
increased the number of drugs," said Van Savage, the study's other
senior author and a UCLA professor of ecology and evolutionary biology
and of biomathematics. "People may think they know how drug combinations
will interact, but they really don't."
On the other hand, 2,331 four-drug combinations and 5,199 five-drug
combinations were less effective than the researchers expected they
would be, said Elif Tekin, the study's lead author, who was a UCLA
postdoctoral scholar during the research.
Some of the four- and five-drug combinations were effective at least
partly because individual medications have different mechanisms for
targeting E. coli. The eight tested by the UCLA researchers work in six unique ways.
"Some drugs attack the cell walls, others attack the DNA inside,"
Savage said. "It's like attacking a castle or fortress. Combining
different methods of attacking may be more effective than just a single
approach."
Said Yeh: "A whole can be much more, or much less, than the sum of
its parts, as we often see with a baseball or basketball team." (As an
example, she cited the decisive upset victory in the 2004 NBA
championship of the Detroit Pistons -- a cohesive team with no
superstars -- over a Los Angeles Lakers team with future Hall of Famers
Kobe Bryant, Shaquille O'Neal, Karl Malone and Gary Payton.)
Yeh added that although the results are very promising, the drug
combinations have been tested in only a laboratory setting and likely
are at least years away from being evaluated as possible treatments for
people.
"With the specter of antibiotic resistance threatening to turn back
health care to the pre-antibiotic era, the ability to more judiciously
use combinations of existing antibiotics that singly are losing potency
is welcome," said Michael Kurilla, director of the Division of Clinical
Innovation at the National Institutes of Health/National Center for
Advancing Translational Sciences. "This work will accelerate the testing
in humans of promising antibiotic combinations for bacterial infections
that we are ill-equipped to deal with today."
The researchers are creating open-access software based on their work
that they plan to make available to other scientists next year. The
software will enable other researchers to analyze the different
combinations of antibiotics studied by the UCLA biologists, and to input
data from their own tests of drug combinations.
Using a MAGIC framework
One component of the software is a mathematical formula for analyzing
how multiple factors interact, which the UCLA scientists developed as
part of their research. They call the framework "mathematical analysis
for general interactions of components," or MAGIC.
"We think MAGIC is a generalizable tool that can be applied to other
diseases -- including cancers -- and in many other areas with three or
more interacting components, to better understand how a complex system
works," Tekin said.
Savage said he plans to use concepts from that framework in his
ongoing research on how temperature, rain, light and other factors
affect the Amazon rainforests.
He, Yeh and Mirta Galesic, a professor of human social dynamics at
the Santa Fe Institute, also are using MAGIC in a study of how people's
formation of ideas is influenced by their parents, friends, schools,
media and other institutions -- and how those factors interact.
"It fits in perfectly with our interest in interacting components," Yeh said.
Other co-authors of the new study are Cynthia White, a UCLA graduate
who was a research technician while working on the project; Tina Kang, a
UCLA doctoral student; Nina Singh, a student at the University of
Southern California; Mauricio Cruz-Loya, a UCLA doctoral student; and
Robert Damoiseaux, professor of molecular and medical pharmacology, and
director of UCLA's Molecular Screening Shared Resource, a facility with
advanced robotics technology where Tekin, White, and Kang conducted much
of the research.
The research team reported in 2016 that combinations of three
antibiotics can often overcome bacteria's resistance to antibiotics,
even when none of the three antibiotics on its own -- or even two of the
three together -- is effective. The biologists reported in 2017 two
combinations of drugs that are unexpectedly successful in reducing the
growth of E. coli bacteria.
Journal Reference:
- Elif Tekin, Cynthia White, Tina Manzhu Kang, Nina Singh, Mauricio Cruz-Loya, Robert Damoiseaux, Van M. Savage, Pamela J. Yeh. Prevalence and patterns of higher-order drug interactions in Escherichia coli. npj Systems Biology and Applications, 2018; 4 (1) DOI: 10.1038/s41540-018-0069-9
Courtesy: ScienceDaily
No comments:
Post a Comment