title: Uncovering emergent interactions in three-way combinations of stressors.
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.
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA.|Department of Microbiology, Immunology, and Molecular Genetics, The Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Casey
authors.identifier: 0000-0001-9241-2413
authors.initials: C
authors.lastname: Beppler
authors.affiliation: Department of Biomathematics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Elif
authors.identifier: 0000-0001-5432-5511
authors.initials: E
authors.lastname: Tekin
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA.|Department of Microbiology, Immunology, and Molecular Genetics, The Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: White
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Cassandra
authors.initials: C
authors.lastname: McDiarmid
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Vargas
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, The Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miller
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA.|Department of Biomathematics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.|Santa Fe Institute, Santa Fe, NM 87501, USA.
authors.forename: Van M
authors.initials: VM
authors.lastname: Savage
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA pamelayeh@ucla.edu.
authors.forename: Pamela J
authors.identifier: 0000-0002-7264-9509
authors.initials: PJ
authors.lastname: Yeh
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004926:Escherichia coli / Q000254:growth & development*; D008954:Models, Biological; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents
keywords: antagonism; antibiotics; drug resistance; higher-order interactions; multiple stressors; synergy