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- Title
Prevalence and patterns of higher-order drug interactions in Escherichia coli.
- Authors
Tekin, Elif; White, Cynthia; Kang, Tina Manzhu; Singh, Nina; Cruz-Loya, Mauricio; Damoiseaux, Robert; Savage, Van M.; Yeh, Pamela J.
- Abstract
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. Specifically, as more drugs are added, we observe an elevated frequency of net synergy (effect greater than expected based on independent individual effects) and also increased instances of 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. Complex systems: emergent interactions are prevalent in drug combinations Interactions play an important role in determining the dynamics of complex systems yet higher-order interactions that involve more than two components are poorly understood. A research team from University of California, Los Angeles led by Pamela Yeh, use a bacteria system to show that higher-order interactions among antibiotics are prevalent and also that there are systematic patterns in how they occur: the frequency of higher-order interactions increases with the number of components, net interactions tend to be more synergistic, and emergent interactions—arising at specific higher-order levels—tend toward antagonism. By detecting patterns in interactions as the number of drugs increases, they provide a method to handle the combinatorial complexity that results from higher-order interactions, yielding a solid foundation for exploring the patterns and consequences of emergent phenomena in other research areas.
- Subjects
ESCHERICHIA coli; DRUG interactions; ANTIBIOTICS; DRUG synergism; DRUG antagonism
- Publication
NPJ Systems Biology & Applications, 2018, Vol 4, Issue 1, pN.PAG
- ISSN
2056-7189
- Publication type
Article
- DOI
10.1038/s41540-018-0069-9