8,000 Drug Combinations More Effective Than Sum of Component Parts

8,000 Drug Combinations More Effective Than Sum of Component Parts

Treatment of infections of extensively drug-resistant bacteria is now a major challenge and the problem is getting worse. There are fears that healthcare may soon be returned to the era before antibiotics were discovered if new ways of treating bacterial infections are not discovered.

A strain of Salmonella typhi, which causes Typhoid fever, has been discovered to be resistant to five of the six drugs that are used to treat infections. If resistance to Azithromycin is acquired, infections will be untreatable.

Strains of Mycobacterium tuberculosis have been identified that are resistant to all but two classes of drug, and a strain of Neisseria gonorrhoeae – termed super gonorrhoea – has been identified that is similarly resistant to all but one antibiotic used to treat the disease.

One possible solution is to use multiple drugs to fight infections. While the combination of two or more drugs may prove effective in the short term, there is concern that such treatments would offer diminishing returns. Combining several antibiotics could cause the benefits of each drug to be cancelled out, and there is much greater potential for unwanted and potentially harmful drug interactions.

However, a team of researchers at UCLA has conducted a study that has identified thousands of four and five drug combinations that have proven to be highly effective at killing bacteria, with the results of the study showing certain drug combinations are much more effective than the sum of their component parts.

While it is common for combinations of two or three drugs to be used to treat certain infections, the addition of one or two further drugs could be a much more effective way of treating a disease.

For the study, the researchers worked with eight different antibiotics. Various combinations of drugs and concentrations were tested in the lab for their ability to stop the growth of E.Coli. Prior to testing different drug combinations, the researches first assessed how effective they thought the combinations would be.

For the four-drug combos, the researchers found 1,676 combinations that were more effective at stopping the growth of E.Coli than they had predicted, and there were 6,443 combinations of five drugs that performed much better than expected.

The research builds on a previous 2016 study in which the researchers identified a 3-drug combination that was effective at stopping the growth of E.Coli, when each of the drugs was ineffective on its own.

“I was blown away by how many effective combinations there are as we increased the number of drugs,” said Van Savage, UCLA professor of ecology and evolutionary biology and of biomathematics and senior author of the study. “People may think they know how drug combinations will interact, but they really don’t.”

However, not all combinations performed so well. The researchers identified 2,331 four-drug combinations that performed worse than expected, and 5,199 five drug combinations which didn’t perform as well as was thought. These combinations proved less effective than the sum of their parts.

The researchers are currently working on software – called mathematical analysis for general interactions of components or MAGIC – that can be used to analyze possible drug combinations, which will be made available to other researchers in 2019. It is hoped that other researchers can add their own data from drug combination tests to develop a much more comprehensive framework for analyzing interactions between different drugs.

The study – Prevalence and patterns of higher-order drug interactions in Escherichia coli – was recently published in the journal npj Systems Biology and Applications. DOI.org/10.1038/s41540-018-0069-9

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