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Published on: November 19, 2015
Uncovering emergent interactions in three-way combinations of stressors
Casey Beppler1,2, Elif Tekin3, Zhiyuan Mao1,2
1Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA.
Abstract:
Understanding how multiple stressors interact is needed to predict the dynamical outcomes of diverse biological systems, ranging from drug-resistant pathogens that are combated and treated with combination drug therapies to ecosystems impacted by environmental toxicants or disturbances. Nevertheless, extensive studies of higher-order (more than two component) interactions have been lacking. Here, we conduct experiments using 20 three-drug combinations and their effects on the bacterial growth of Escherichia coli We report our measurements of growth rates in single, pairwise and triple-drug combinations. To uncover emergent interactions, we derive a simple framework to calculate expectations for three-way interactions based on the measured impact of each individual stressor and of each pairwise interaction. Using our framework, we find that (i) emergent antagonisms are more common than emergent synergies and (ii) emergent antagonisms are more common and emergent synergies are more rare than would be inferred from measures of net effects that do not disentangle pairwise interactions from three-way interactions.
Insights
Emergent antagonisms are more common than synergies in three-drug combinations impacting bacterial growth. This study reveals complex multi-stressor interactions in Escherichia coli, crucial for understanding drug resistance and ecosystem dynamics.
Area of Science:
- Microbiology
- Systems Biology
- Pharmacology
Background:
- Predicting biological system dynamics requires understanding multi-stressor interactions.
- Higher-order (three or more components) stressor interactions remain understudied.
- Applications range from combination drug therapies to ecosystem toxicology.
Purpose of the Study:
- To investigate higher-order interactions of three-drug combinations on bacterial growth.
- To develop a framework for analyzing emergent three-way interactions.
- To quantify the frequency of emergent synergism and antagonism.
Main Methods:
- Experimental measurement of Escherichia coli growth rates under single, pairwise, and triple-drug combinations.
- Derivation of a framework to predict three-way interaction expectations from lower-order effects.
- Comparison of emergent interactions with net effects.
Main Results:
- Emergent antagonisms were found to be more frequent than emergent synergies.
- The frequency of emergent antagonisms and rare emergent synergies differs from predictions based on net effects alone.
- A framework was established to disentangle pairwise from three-way interactions.
Conclusions:
- Emergent antagonisms are prevalent in complex drug interactions.
- Net effect measures can obscure the true nature of higher-order interactions.
- Accurate prediction of multi-stressor outcomes necessitates disentangling interaction orders.
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