Sum of terms
8,000 new combinations of antibiotics have been surprisingly effective
Previously, scientists believed that the simultaneous use of more than two antibacterial drugs would lead to a decrease in the positive effect. The prevailing theory was that the additional benefits of combining three or more drugs would be too small, or that, eventually, one most effective drug would stand out, and it would be wiser to abandon the others.
Now a group of biologists from the University of California at Los Angeles has discovered thousands of combinations of four and five drugs that are extremely effective in killing harmful bacteria. These findings are very important for protecting public health in a situation where pathogens and common infections are becoming increasingly resistant to antibiotics.
Article by Tekin et al. The prevalence and patterns of higher-order drug interactions in Escherichia coli is published in the journal npj Systems Biology and Applications – VM.
"There is a tradition of using only one or maybe two drugs," she said Pamela Ye, one of the senior authors of the study, and associate professor of Ecology and Evolutionary Biology at the University of California. – We offer an alternative that looks very promising: we should not limit ourselves to just one drug or combinations of two antibiotics in the medical arsenal. We expect some of the combinations to work much better than existing antibiotics alone."
Working with eight antibiotics, the researchers analyzed how all kinds of combinations of four and five drugs, including in different dosages – a total of 18,278 combinations – can fight E. coli. They expected that some of the combinations would be very effective at killing bacteria, but were amazed at how many powerful combinations they found.
First, the researchers predicted the effectiveness of each combination in blocking the growth of E. coli. Among the combinations of four drugs, there were 1,676 groups that coped better than scientists expected. Among the combinations of five drugs, 6443 were more effective than expected.
"I was shocked by how many effective combinations we got by increasing the number of drugs," said Van Savage, senior author of the study, professor of ecology, evolutionary biology and biomathematics at the University of California. "People may think they know how drugs interact in combination, but in fact they don't."
On the other hand, 2,331 combinations of four drugs and 5,199 combinations of five were less effective than the researchers expected," said Elif Tekin, lead author of the study.
Some combinations of four and five drugs were effective, at least in part, because individual drugs had different targeting mechanisms for E. coli. The eight combinations tested by the researchers had six unique exposure pathways.
"Some drugs attack cell walls, others DNA from the inside," Savage said. "It's like attacking a castle or a fortress. Combining different methods of attack can be more effective than using a single approach."
Pamela Ye suggested the association: "The whole can be much larger or much smaller than the sum of its parts, as often happens with a baseball or basketball team." (As an example, she cited the decisive victory in 2004 in the NBA of the Detroit Pistons – a close–knit team without superstars - over the Los Angeles Lakers team, which became the hall of fame of Kobe Bryant, Shaquille O'Neal, Karl Malone and Gary Payton).
Ye added that although the results are very promising, the drug combinations have only been tested in laboratory conditions and there are probably at least a few years until they start being tested on humans.
"With the emergence of antibiotic resistance threatening to bring medical care back to the pre–antibiotic era, the ability to use combinations of existing drugs that are individually losing their power more intelligently is welcome," said Michael Kurilla, director of clinical innovation at the National Institutes of Health/National Center for the Advancement of Translational Science. "This work will accelerate the testing of promising combinations of antibiotics in humans, targeting bacterial infections, for which we are poorly equipped to fight today."
Researchers are creating open-access software based on their work, which they plan to provide to other scientists next year. The software will allow other scientists to analyze various combinations of antibiotics studied by biologists at the University of California and enter data from their own studies of drug combinations.
Using the MAGIC Structure
One of the components of the software is a mathematical formula for analyzing the interaction of several factors, which scientists have developed as part of research. They call it "mathematical analysis for general interactions of components" ("mathematical analysis for general interactions of components"), or MAGIC.
"We believe that MAGIC is a universal tool that can be applied to other diseases, including cancer, 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 this framework in ongoing research on the effects of temperature, rain, light and other factors on the Amazon rainforest.
He, Ye and Mirta Galesik, a professor of human social dynamics at the Santa Fe Institute, also use MAGIC to study how people's ideas are influenced by their parents, friends, schools, media and other institutions – and how these factors interact.
"This method fits perfectly with our interest in interacting components," Ye said.
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