New antibiotics that work | University of California

Scientists have traditionally believed that combining more than two drugs to fight harmful bacteria would produce diminishing returns. The prevailing theory is that the additional benefits of combining three or more medications would be too small to be significant or that interactions between drugs would eliminate their benefits.

Today, a team of UCLA biologists has discovered thousands of combinations of four- and five-drug antibiotics that are more effective at removing harmful bacteria than suggested by the most currents. Their findings, reported in the journal Systems Biology and Applications, could be a major step towards protecting public health at a time when common pathogens and infections are becoming increasingly resistant to antibiotics.

"It's traditional to use just one drug, maybe two," said Pamela Yeh, one of the lead authors of the study and an assistant professor of ecology and evolutionary biology at UCLA . "We offer a very promising alternative. We should not limit ourselves to single or dual drug combinations in our medical toolbox. We expect that many of these combinations, or more, will work much better than existing antibiotics.

Working with eight antibiotics, the researchers analyzed how all possible combinations of four and five drugs, including many different doses – a total of 18,278 combinations – acted against E. coli. They hoped that some of the combinations would be very effective at killing the bacteria, but they were surprised by the number of powerful combinations that they discovered.

For each combination tested, the researchers first predicted the efficiency with which they thought they could stop the growth of E. Coli. Of the four-drug combinations, 1,676 groups performed better than expected. Of the five drug combinations, 6,443 groups were more effective than expected.

More than the sum of its parts

"I was blown away by the number of effective combinations as we increased the number of medications," said Van Savage, another lead author of the study and professor of ecology, evolutionary biology and of biomathematics at UCLA. "People may think that they know how drug combinations will interact, but they do not really do it."

In addition, 2,331 four-drug combinations and 5,199 five-drug combinations were less effective than the researchers expected, said Elif Tekin, lead author of the study, a postdoctoral fellow at the University of California .

Some of the four- and five-drug combinations have been effective at least in part because individual drugs have different mechanisms for targeting E. coli. The eight tested by UCLA researchers work in six different ways.

"Some drugs attack the cell walls, others attack the DNA inside," Savage said. "It's like attacking a castle or a fortress. Combining different attack methods may be more effective than one approach. "

Yeh said, "A set can be a lot more or a lot less than the sum of its parts, as we often see with a baseball or basketball team." (For example, she cited the victory The 2004 Detroit Pistons NBA championship – a cohesive team without superstars – faces a Los Angeles Lakers team with future Hall of Fame member 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 a lab only and are probably at least years of evaluation as possible treatments for people.

"With the specter of antibiotic resistance threatening to bring health care back to the pre-antibiotic era, the ability to more wisely use combinations of existing antibiotics that are losing potency is welcome, "said Michael Kurilla, director of the Division of Clinical Innovation at the National Institutes of Health / National Center for the Advancement of Translational Sciences. "This work will speed up human testing of promising antibiotic combinations for bacterial infections that we are ill equipped to cope with today."

Researchers are creating open source software based on their work that they plan to make available to other scientists next year. The software will allow other researchers to analyze the different combinations of antibiotics studied by UCLA biologists and capture data from their own drug combination tests.

Use a MAGIC framework

One of the components of the software is a mathematical formula for analyzing the interaction of several factors, which UCLA scientists have developed as part of their research. They call the framework "mathematical analysis of the general interactions of components" or MAGIC.

"We believe that MAGIC is a generalizable tool that can be applied to other diseases – including cancers – and in many other areas with three or more interactive components, to better understand how a system works. complex, "said Tekin.

Savage said that he planned to use the concepts of this framework in his ongoing research on how temperature, rain, light and other factors affect the Amazon rainforests.

He, Yeh and Mirta Galesic, Professor of Human Social Dynamics at the Santa Fe Institute, also use MAGIC to study the influence of their parents, friends, schools, media and other institutions on the formation of ideas – and how these the factors interact.

"This fits perfectly with our interest in interactive components," said Yeh.

The other co-authors of the new study are Cynthia White, a graduate of UCLA who was a research technician while she was working on the project; Tina Kang, a PhD student from UCLA; Nina Singh, student at the University of Southern California; Mauricio Cruz-Loya, Ph.D. student at UCLA; and Robert Damoiseaux, Professor of Molecular and Medical Pharmacology and Director of UCLA's Molecular Screening Shared Resource, a facility with advanced robotic technology where Tekin, White, and Kang have conducted much of the research.

The research team reported in 2016 that combinations of three antibiotics can often overcome bacterial resistance to antibiotics, even though none of the three antibiotics taken alone – or even two of the three at the same time – is effective. Biologists reported in 2017 two drug combinations that unexpectedly succeed in reducing the growth of E. coli bacteria.

The research was funded by the James S. McDonnell Foundation Complex Systems Award, the National Science Foundation, the Hellman Foundation, the National Institutes of Health / National Center for the Advancement of Translation Sciences and the award UCLA