Combining 4 to 5 Antibiotics can Help Kill Harmful Bacteria

Four- and five-drug combinations of antibiotics used in a laboratory setting by UCLA biologists were more effective at killing harmful bacteria than earlier views had suggested. Up until now, scientists believed that combining more than two drugs to fight harmful bacteria would be less effective than a single or two-drug treatment – maybe because the margin of benefits offered by three or more drugs would be trivial compared to those by a lesser number of drugs. There are also more chances of drug-drug interactions when using an increasing number of drugs which might cancel out their benefits.

In an era where pathogens and common infections are increasingly becoming resistant to antibiotics, the current study has contributed a significant step toward protecting public health. The findings have been reported in the journal npj Systems Biology and Applications.

"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."

The researchers chose eight antibiotics and analyzed how every possible four- and five-drug combination worked against the bacteria Escherichia coli (E. Coli).

The eight tested drugs work in six unique ways – some attack the cell walls while others attack the DNA inside.

There were a total of 18,278 combinations in all in varying doses. Expecting only some of the combinations to be very effective at killing the bacteria, they were startled at the number of potent combinations they discovered.

• A total of 1,676 groupings of drugs among the four-drug combinations they tried were more effective in stopping the growth of E. coli than what they had predicted would be the result
• A total of 6,443 groupings of drugs among the five-drug combinations were more effective than the anticipated numbers

"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."

• Some of the combinations were only partly effective owing to the different mechanisms of the individual medications for targeting E. coli
• Finally, 2,331 four-drug combinations and 5,199 five-drug combinations were less effective than the expected numbers

Yeh said that the study is an example of how sometimes a whole can be much more, or much less, than the sum of its parts; she also added that since these promising results have only been seen in a laboratory setting, they are at least years away from being evaluated as possible treatments for people.

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"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 Science. "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 MAGIC framework

The research team are creating open-access software based on their work to be available to other scientists next year that will enable the latter to analyze the different combinations of antibiotics studied by the UCLA biologists and to input data from their drug combination experiments.

The software includes a mathematical formula for analyzing how multiple factors interact. The UCLA scientists call the framework "mathematical analysis for general interactions of components (MAGIC)”.

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According to the UCLA scientists, MAGIC is a generalizable tool that can be applied to other diseases like cancers where three or more interacting components are present to help understand how a complex system works.

For example, Savage is using concepts from MAGIC in his ongoing research on how elements like rain, temperature, light and other factors can affect the Amazon rainforests.

Yeh, Savage and a professor from the Santa Fe Institute are using MAGIC to unravel how a person’s ideas can be influenced by their parents, friends, schools, media and other institutions and the interactions of these factors.

Earlier reports by the scientists who have worked on this study had focused on combinations of three antibiotics to overcome bacteria's resistance to antibiotics, even when each of them or two of them together were not effective. Another one had shown an unexpected success in reducing E. coli growth by two combinations of drugs.

Hence, it might be worthwhile to use antibiotic combinations going forward especially when individual antibiotics are losing their potency, and if we are lucky we might well be on the path to curbing antibiotic resistance!

Reference:

1. More firepower: 8000 new antibiotic combos on the anvil - (https://expressuk.org/news/firepower-8000-new-antibiotic-combos-anvil)

Source-Medindia