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Prevalence and patterns of higher-order interactions

By Elif Tekin, Cynthia White, Tina Manzhu Kang, Nina Singh, Mauricio Cruz-Loya, Robert Damoiseaux, Van M Savage, Pamela J Yeh

Posted 14 Dec 2017
bioRxiv DOI: 10.1101/233312 (published DOI: 10.1038/s41540-018-0069-9)

Interactions and emergent processes are essential for research on complex systems involving many components. Most studies focus solely on pairwise interactions and ignore higher-order interactions among three or more components. To gain deeper insights into higher-order interactions and complex environments, we study antibiotic combinations applied to pathogenic Escherichia coli and obtain unprecedented amounts of detailed data (251 two-drug combinations, 1512 three-drug combinations, 5670 four-drug combinations, and 13608 five-drug combinations). Directly opposite to previous assumptions and reports, we find higher-order interactions increase in frequency with the number of drugs in the bacteria's environment. Furthermore, we observe a shift towards net synergy (effect greater than expected based on independent individual effects) and towards emergent antagonism (effect less than expected based on lower-order interaction effects). These findings have implications for the potential efficacy of drug combinations and are crucial for better navigating problems associated with the combinatorial complexity of multi-component systems.

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