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.

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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